Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB...Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB i.e. multiple-drug resistance tuberculosis, XDR-TB i.e. extensively-drug resistance tuberculosis & TDR-TB i.e. total-drug resistance tuberculosis has forwarded an urgent need to discover novel antitubercular agents. The current work is aimed at combining two previously well-known pharmacophores (pyrazoline and benzoxazole nucleus) in order to design and synthesize a series of novel benzoxazole-based pyrazoline derivatives. The synthesized target compounds were structurally confirmed by LCMS, 1H-NMR and 13C-NMR analysis. The target compounds were In vitro evaluated against M. tuberculosis H37Rv strain, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. The In vitro screening results depicted that majority of the target compounds displayed potent activity with MIC in a range of ~0.8 to 6.25 μg/mL. Many compounds were found to be more potent than isoniazid against MDR-TB with MIC value 3.12 μg/mL and XDR-TB with MIC value 12.5 μg/mL. Cytotoxicity assay of these active compounds on VERO cell lines also displayed good selectivity index.展开更多
Bioinformatics,an interdisciplinary field that integrates computer science,biology,information technology,and statistics,plays a pivotal role in analyzing and interpreting biological data.It has become an indispensabl...Bioinformatics,an interdisciplinary field that integrates computer science,biology,information technology,and statistics,plays a pivotal role in analyzing and interpreting biological data.It has become an indispensable tool in the design and discovery of novel drugs by facilitating the analysis of biological datasets and aiding in the identification of potential therapeutic targets.With the rise of antibiotic resistance among bacterial species,the demand for new drug development has intensified.However,the process of drug discovery remains labor-intensive,costly,and time-consuming.The identification of new drugs involves multiple critical stages,including target identification,structural analysis of the target protein,selection of potential drug candidates,safety and efficacy assessments,drug optimization,and ultimately,validation.Bioinformatics contributes significantly to each of these phases.For instance,through the analysis of protein sequences and genetic data,researchers can pinpoint potential drug targets.Once a target protein is identified,bioinformatics tools enable detailed structural analysis of the protein.Upon locating the potential ligand-binding site,large compound databases can be screened to discover viable drug candidates.Simulations further aid in examining the interaction between the target protein and biomolecules,providing valuable insights into the drug’s safety and efficacy.Moreover,bioinformatics-driven drug optimization helps improve both safety and effectiveness.Recent advances,such as pharmacophore modeling and molecular docking techniques,have accelerated the screening process,narrowing thousands of candidate molecules down to a select few with promising therapeutic potential.In this study,bioinformatics was leveraged within the framework of network pharmacology to design and discover new drugs.展开更多
Pharmacophore is a commonly used method for molecular simulation, including ligand-based pharmacophore （LBP） and structure-based pharmacophore （SBP）. LBP can be utilized to identify active compounds usual with low...Pharmacophore is a commonly used method for molecular simulation, including ligand-based pharmacophore （LBP） and structure-based pharmacophore （SBP）. LBP can be utilized to identify active compounds usual with lower accuracy, and SBP is able to use for distin- guishing active compounds from inactive compounds with frequently higher missing rates. Merged pharmacophore （MP） is presented to integrate advantages and avoid shortcomings of LBP and SBP. In this work, LBP and SBP models were constructed for the study of per- oxisome proliferator receptor-alpha （PPARα） agonists. According to the comparison of the two types of pharmacophore models, mainly and secondarily pharmacological features were identified. The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model. Then, the reliability and screening efficiency of the best MP model were validated by three databases. The best MP model was utilized to compute PPARα activity of compounds from traditional Chinese medicine. The screening efficiency of MP model outperformed individual LBP or SBP model for PPARα agonists, and was similar to combinatorial screening of LBP and SBP. However, MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP, which would be beneficial to guide drug design and optimization.展开更多
Objective： To explore the molecular basis of the effects of Gancao （Radix Glycyrrhizae, GC） on inflammation throughthe inhibition of cyclooxygenase 2 （COX-2）. Methods： The Discovery Studio 4.5 System was used to...Objective： To explore the molecular basis of the effects of Gancao （Radix Glycyrrhizae, GC） on inflammation throughthe inhibition of cyclooxygenase 2 （COX-2）. Methods： The Discovery Studio 4.5 System was used to predict thephysicochemical properties of GC molecular compounds. The Ligand Profiler was used to screen for natural GCcomponents that could combine with the COX-2 pharmacophores. The AutoDock Vina 1.1.2 software was used for themolecular docking of the natural GC components with the COX-2 protein. Results： The aromatics were the closest to thenon-steroidal anti-inflammatory drugs in terms of the three properties, namely molecular weight, molecular surface area,and molecular solubility, followed by the flavonoids; whereas the terpenoids/saponins differed most from thenon-steroidal anti-inflammatory drugs in terms of the three properties; and the aliphatics were inconsistent. One hundredand eighteen small molecules were obtained through the pharmacophore screening using GC. The molecular bindingenergy （MBE） results demonstrated that the MBE value of the flavonoids/aromatics, obtained from their binding with theCOX-2 protein, was lower than that obtained from their binding with the substrate, metabolism of arachidonic acid,whereas the MBE value of the aliphatics/terpenoids, obtained from their binding with the COX-2 protein, was higherthan that obtained from their binding with the substrate, arachidonic acid. Finally, further filtration, based on thephysicochemical properties and the molecular binding energies of the small molecules, was carried out. Forty-twonatural GC components, including 35 flavonoid and 7 aromatic constituents, with low binding energies and potentialinhibitory effects on COX-2, were screened. Conclusion： Using the three-step program, pharmacophore screening,molecular docking, and physicochemical properties analysis, we screened out 35 flavonoid molecules and 7 aromaticmolecules, which may be potential COX-2 inhibitors, from GC. Two of the 35 flavonoid molecules （licochalcone A andglabridin） have been confirmed in the laboratory to have inhibitory effects on COX-2. Our findings provide a materialbasis for the development of non-steroidal GC drugs.展开更多
A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate)....A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate). These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property (drug-ability) challenges and liability noted in ACP 4 and 5. A pseudo-Robinson annulation protocol was used to furnish this new class of potential antibiotics. Structure-activity relationship (SAR) study was done to identify the pharmacophore(s) in this molecular scaffold. A selection of these compounds was used in our preliminary antibacterial inhibitory activities’ studies on Bacillus mycoides and Bacillus subtilis. These preliminary studies show that the TACCs exhibited equal, and in some cases better, antibacterial activity than ACP 4 and 5.展开更多
The 3VHE protein is considered as a potential target for the treatment of prostate cancer. In order to find new 3VHE inhibitors, pharmacophore models based on the molecular structure of rhodanine derivatives and a thr...The 3VHE protein is considered as a potential target for the treatment of prostate cancer. In order to find new 3VHE inhibitors, pharmacophore models based on the molecular structure of rhodanine derivatives and a three-dimensional quantitative structure-activity relationship model (3D-QSAR) have been developed and validated by different methods. The 3D-QSAR model was evaluated for its predictive performance on a diverse test set containing 18 prostate cancer inhibitors. It presents very interesting internal and external statistical validation parameters (SD = 0.081;R2 = 0.903;Q2 = 0.869;;F = 247.2). This result suggests that the 3D-QSAR combinatorial model can be used to search for new 3VHE inhibitors and predict their potential activity. Based on the combinatorial pharmacophore model, a virtual screening of the Enamine database was performed. Compounds selected after virtual screening were subjected to molecular docking protocols (HTVS, SP, XP and IFD). Twenty new active compounds have been identified and their absorption, distribution, metabolism and excretion (ADME) property calculated using Schr?dinger’s Qikprop module. These results suggest that these new compounds could constitute new chemical starting points for further structural optimization of 3VHE inhibitors.展开更多
Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure...Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure ofα7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher＇s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.展开更多
5-HT1A receptor is a crucial therapeutic target for the treatment of anxiety, depression, pain, etc. Design and preparation of potent 5-HT1A receptor ligands for drug discovery has attracted extensive attention in the...5-HT1A receptor is a crucial therapeutic target for the treatment of anxiety, depression, pain, etc. Design and preparation of potent 5-HT1A receptor ligands for drug discovery has attracted extensive attention in the past few years. In this paper, a three dimensional model of human 5-HT1A receptor was constructed by means of homology modeling. And the docking of MP349 to the receptor suggested a reliable binding mode for 5-HT1A receptor ligand. Based on this ligand-receptor binding mode, an elaborate receptor structure based pharmacophore model was established, which revealed many important features responsible for ligand and 5-HT1A receptor interactions. A virtual screening experiment verified the ability of this pharmacophore model to discover true 5-HT1A receptor ligand. The results of this research would provide important information for further optimizations of 5-HT1A receptor ligands and guide related new lead discoveries.展开更多
Naodesheng(NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemi...Naodesheng(NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease(AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target-biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods.展开更多
To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the...To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists.展开更多
Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The ...Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The pathway analyses for the collection of anticancer targets screened were carried out based on the KEGG pathway database, followed by the forecast of potential pharmacological activities and pathways of the effects of cryptotanshinone, and verification of some of the targets screened using whole cell tests. The results showed that a total of eight targets with anticancer potential were screened, including MAP2K1, RARα, RXRα, PDK1, CHK1, AR, Ang-1 R, and Kif11. These targets are mainly related to four aspects of the cancer growth: the cell cycle, angiogenesis, apoptosis, and androgen receptor. The cell tests showed that cryptotanshinone can inhibit the viability of human hepatoma cells SMMC-7721, which is related to the reduction of expression of MAP2K1 mRNA. This method provides a strong clue for the study of the anticancer effects and mechanisms of action of cryptotanshinone in the future.展开更多
The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disr...The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.展开更多
Multidrug resistance-associated proteins （MRPs） can effiux structurally diverse drugs, drug conjugates, drug metabolites, as well as other small molecules out of the cells, and this is the main cause of producing mu...Multidrug resistance-associated proteins （MRPs） can effiux structurally diverse drugs, drug conjugates, drug metabolites, as well as other small molecules out of the cells, and this is the main cause of producing multidrug resistance （MDR） of some anticaneer drugs. Therefore, it is crucial to uncover the molecular features of MRPs substrates in developing anti-MDR cancer therapy. In the present study, common feature pharmacophore models were developed by employing CATALYST Pharmacophore Modeling and Analysis tools using substrates of MRPs, including MRP1, -2, -3, -4, -5, -6, -8 and MRPs family, respectively. The models were validated using independent decoy sets generated in DUD-E, and the ones with best A UC （area under the curve） scores were chosen to predict endogenous substrates by screening the Human Metabolome Database （HMDB）. A number of molecules obtained by pharmacophore screening have been validated in the literatures. By comparing physical properties （ALOGP, Molecular_PolarSurfaceArea, Molecular_Volume, Molecular_Weight, Num H Acceptors, Num H Donors） and scaffold features of the screened candidates with the known substrates, we found that： 1） The two sets have consistent ALOGP, Molecule_Volume and Molecule_Weight distribution trend; 2） Substrates of MRP1 have a better lipophilicity than the other subtypes, which is consistent with the two hydrophobic centers on the MRP1 pharmacophore; 3） In the aspect of the scaffold structures, they have the identical or similar backbone fragments.展开更多
The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused...The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.展开更多
Cholesteryl ester transfer protein （CETP） is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol （HDL-C） levels and increasing low-density lipoprotein cholesterol ...Cholesteryl ester transfer protein （CETP） is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol （HDL-C） levels and increasing low-density lipoprotein cholesterol （LDL-C） levels. Inhibition of CETP may be a new therapy for treating atherosclerosis. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H-10 as a potential CETP inhibitor in vitro. Based on H-10, a series of 3-（（3,4-dichlorophenyl）（4-substituted benzyl）amino） propanamides were designed, synthesized, and evaluated against CETP. Compound 41 was found to have the best activity, resulting in 85.0% inhibition of CETP at l0 μmol/L.展开更多
Fentanyl is a highly selective u-opioid receptor agonist with high analgesic activity. Three-dimensional pharmacophore models were built from a set of 50 fentanyl derivatives. These were employed to elucidate ligand-r...Fentanyl is a highly selective u-opioid receptor agonist with high analgesic activity. Three-dimensional pharmacophore models were built from a set of 50 fentanyl derivatives. These were employed to elucidate ligand-receptor interactions using information derived only from the ligand structure to identify new potential lead compounds. The present studies demonstrated that three hydrophobic regions, one positive ionizable region and two hydrogen bond acceptor region sites located on the molecule seem to be essential for analgesic activity. The results of the comparative molecular field analysis model suggested that both steric and electrostatic interactions play important roles. The contributions from steric and electrostatic fields for the model were 0.621 and 0.379, respectively. The pharmacophore model provides crucial information about how well the common features of a subject molecule overlap with the hypothesis model, which is very valuable for designing and optimizing new active structures.展开更多
Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and cl...Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and clinical therapy.In this study,we investigated the relationship between transient receptor potential melastatin 8(TRPM8)and pungent flavor using three-dimensional pharmacophores based on virtual screening methods.Methods:Firstly,an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation.Then,several therapeutic targets,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoAR),cholesteryl ester transfer protein(CETP),Niemann-Pick C1-Like 1(NPC1L1)and platelet-activating factor receptor(PAFR),were selected to screen traditional Chinese herbs,and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets.Results:According to the screening results,TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8,which shares the common virtual screening hits with the therapeutic targets,was considered to be related to the action of pungent taste.Conclusion:The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.展开更多
Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new thera...Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM) due to its non-insulin related characteristics with less side effects. Current commercially available hSGLT2 inhibitors are all C-glycoside inhibitors. Previous studies have reported that N-glycoside inhibitors have better potential to serve as new drugs due to their good metabolic stability. In addition, non-glycoside inhibitors have been shown to exhibit the capability to overcome the existing problems of current glycoside inhibitors, including low tissue permeability, poor stability and short serum half-time. Here, we aimed to discover novel N-glycoside and non-glycoside hSGLT2 inhibitors by a combination of several computational approaches. A ligand-based pharmacophore model was generated, well validated and subsequently utilized as a 3D query to identify novel hSGLT2 inhibitors from National Cancer Institute (NCI) and Traditional Chinese Medicine (TCM) databases. Finally, one N-glycoside (NSC679207) and one non-glycoside (TCM_Piperenol_A) hSGLT2 inhibitors were successfully identified, which were proven to exhibit excellent binding affinities, pharmacokinetic properties and less toxicity than the commercially available hSGLT2 inhibitor, canagliflozin, via molecular docking, ADMET prediction, molecular dynamics (MD) simulations and binding free energy calculations. All together, our results strongly suggest that these two compounds have great potential to serve as novel hSGLT2 inhibitors for the treatment of T2DM and their efficacies may be further examined by a series of in vitro and/or in vivo bioassays.展开更多
4-Hydroxyphenylpyruvate dioxygenase(EC 1.13.11.27,HPPD)is currently one of the popular targets of herbicide research,and herbicides targeting it have shown promising results in treating resistant weeds.However,the lon...4-Hydroxyphenylpyruvate dioxygenase(EC 1.13.11.27,HPPD)is currently one of the popular targets of herbicide research,and herbicides targeting it have shown promising results in treating resistant weeds.However,the longterm application of HPPD inhibitors with in their classical scaffolds inevitably leads to the development of drug resistance.To further delay the underlying development of weed resistance to HPPD inhibitors,we successfully screened HPPD inhibitor pharmacophore with novel chelate structures using computer-aided drug molecular design and obtained 2-trifluoromethyltetrazolium nicotinamide derivatives through active fragment splicing.Among these derivatives,6-(3,3-diethyl-1-methylureido)-N-(1-methyl-1H-tetrazol-5-yl)-2-(trifluoromethyl)nicotinamide(compound 31),exhibited the most promising in vitro enzyme inhibitory activity,with IC_(50) value of 0.072μM,which was approximately five times better than that of the control agent mesotrione(IC_(50)?0.363μM).The crystal structure of the AtHPPD complexed with compound 31(2.0Å)and the binding energy calculations of the representative compounds revealed several important interactions of the ligand binding to the target protein,which explained the superior enzyme inhibitory activity of the compounds at the molecular level.In addition,compounds 7 and 31 possessed 100%inhibition against the five target weeds at the tested dosage and both were more effective against Setaria viridis than mesotrione.In general,it is promising to design novel HPPD inhibitors by developing novel chelating structures,and compounds 7 or 31 could be used as the leads for further development of valuable HPPD inhibitors.展开更多
OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophor...OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophore model from a set of TACE-selective inhibitor using the Common Feature Pharmacophore Model protocol implemented in Discovery Studio 3.1.1.A fluorimetric assay was used to investigate the potential ability of compounds to inhibit TACE enzymatic activity.The ability of compound 1 to inhibit TACE activity in a human monocyte THP-1 cell line was evaluated by ELISA.RESULTS In this study,apharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds,from which compound 1 emerged as a top candidate.In a cell-free assay,compound 1inhibited TACE enzymatic activity in a dose-dependent manner.Moreover,compound 1 inhibited the production of soluble TNF-αin human acute monocytic leukemia THP-1 cells without impacting nitric oxide production,and exhibited anti-proliferative activity against THP-1cells.CONCLUSION Compound 1 was found to inhibit TACE enzymatic activity in a cell-free system and LPS-induced TNF-αsecretion in cellulo.We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors.展开更多
文摘Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB i.e. multiple-drug resistance tuberculosis, XDR-TB i.e. extensively-drug resistance tuberculosis & TDR-TB i.e. total-drug resistance tuberculosis has forwarded an urgent need to discover novel antitubercular agents. The current work is aimed at combining two previously well-known pharmacophores (pyrazoline and benzoxazole nucleus) in order to design and synthesize a series of novel benzoxazole-based pyrazoline derivatives. The synthesized target compounds were structurally confirmed by LCMS, 1H-NMR and 13C-NMR analysis. The target compounds were In vitro evaluated against M. tuberculosis H37Rv strain, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. The In vitro screening results depicted that majority of the target compounds displayed potent activity with MIC in a range of ~0.8 to 6.25 μg/mL. Many compounds were found to be more potent than isoniazid against MDR-TB with MIC value 3.12 μg/mL and XDR-TB with MIC value 12.5 μg/mL. Cytotoxicity assay of these active compounds on VERO cell lines also displayed good selectivity index.
文摘Bioinformatics,an interdisciplinary field that integrates computer science,biology,information technology,and statistics,plays a pivotal role in analyzing and interpreting biological data.It has become an indispensable tool in the design and discovery of novel drugs by facilitating the analysis of biological datasets and aiding in the identification of potential therapeutic targets.With the rise of antibiotic resistance among bacterial species,the demand for new drug development has intensified.However,the process of drug discovery remains labor-intensive,costly,and time-consuming.The identification of new drugs involves multiple critical stages,including target identification,structural analysis of the target protein,selection of potential drug candidates,safety and efficacy assessments,drug optimization,and ultimately,validation.Bioinformatics contributes significantly to each of these phases.For instance,through the analysis of protein sequences and genetic data,researchers can pinpoint potential drug targets.Once a target protein is identified,bioinformatics tools enable detailed structural analysis of the protein.Upon locating the potential ligand-binding site,large compound databases can be screened to discover viable drug candidates.Simulations further aid in examining the interaction between the target protein and biomolecules,providing valuable insights into the drug’s safety and efficacy.Moreover,bioinformatics-driven drug optimization helps improve both safety and effectiveness.Recent advances,such as pharmacophore modeling and molecular docking techniques,have accelerated the screening process,narrowing thousands of candidate molecules down to a select few with promising therapeutic potential.In this study,bioinformatics was leveraged within the framework of network pharmacology to design and discover new drugs.
文摘Pharmacophore is a commonly used method for molecular simulation, including ligand-based pharmacophore （LBP） and structure-based pharmacophore （SBP）. LBP can be utilized to identify active compounds usual with lower accuracy, and SBP is able to use for distin- guishing active compounds from inactive compounds with frequently higher missing rates. Merged pharmacophore （MP） is presented to integrate advantages and avoid shortcomings of LBP and SBP. In this work, LBP and SBP models were constructed for the study of per- oxisome proliferator receptor-alpha （PPARα） agonists. According to the comparison of the two types of pharmacophore models, mainly and secondarily pharmacological features were identified. The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model. Then, the reliability and screening efficiency of the best MP model were validated by three databases. The best MP model was utilized to compute PPARα activity of compounds from traditional Chinese medicine. The screening efficiency of MP model outperformed individual LBP or SBP model for PPARα agonists, and was similar to combinatorial screening of LBP and SBP. However, MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP, which would be beneficial to guide drug design and optimization.
文摘Objective： To explore the molecular basis of the effects of Gancao （Radix Glycyrrhizae, GC） on inflammation throughthe inhibition of cyclooxygenase 2 （COX-2）. Methods： The Discovery Studio 4.5 System was used to predict thephysicochemical properties of GC molecular compounds. The Ligand Profiler was used to screen for natural GCcomponents that could combine with the COX-2 pharmacophores. The AutoDock Vina 1.1.2 software was used for themolecular docking of the natural GC components with the COX-2 protein. Results： The aromatics were the closest to thenon-steroidal anti-inflammatory drugs in terms of the three properties, namely molecular weight, molecular surface area,and molecular solubility, followed by the flavonoids; whereas the terpenoids/saponins differed most from thenon-steroidal anti-inflammatory drugs in terms of the three properties; and the aliphatics were inconsistent. One hundredand eighteen small molecules were obtained through the pharmacophore screening using GC. The molecular bindingenergy （MBE） results demonstrated that the MBE value of the flavonoids/aromatics, obtained from their binding with theCOX-2 protein, was lower than that obtained from their binding with the substrate, metabolism of arachidonic acid,whereas the MBE value of the aliphatics/terpenoids, obtained from their binding with the COX-2 protein, was higherthan that obtained from their binding with the substrate, arachidonic acid. Finally, further filtration, based on thephysicochemical properties and the molecular binding energies of the small molecules, was carried out. Forty-twonatural GC components, including 35 flavonoid and 7 aromatic constituents, with low binding energies and potentialinhibitory effects on COX-2, were screened. Conclusion： Using the three-step program, pharmacophore screening,molecular docking, and physicochemical properties analysis, we screened out 35 flavonoid molecules and 7 aromaticmolecules, which may be potential COX-2 inhibitors, from GC. Two of the 35 flavonoid molecules （licochalcone A andglabridin） have been confirmed in the laboratory to have inhibitory effects on COX-2. Our findings provide a materialbasis for the development of non-steroidal GC drugs.
文摘A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate). These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property (drug-ability) challenges and liability noted in ACP 4 and 5. A pseudo-Robinson annulation protocol was used to furnish this new class of potential antibiotics. Structure-activity relationship (SAR) study was done to identify the pharmacophore(s) in this molecular scaffold. A selection of these compounds was used in our preliminary antibacterial inhibitory activities’ studies on Bacillus mycoides and Bacillus subtilis. These preliminary studies show that the TACCs exhibited equal, and in some cases better, antibacterial activity than ACP 4 and 5.
文摘The 3VHE protein is considered as a potential target for the treatment of prostate cancer. In order to find new 3VHE inhibitors, pharmacophore models based on the molecular structure of rhodanine derivatives and a three-dimensional quantitative structure-activity relationship model (3D-QSAR) have been developed and validated by different methods. The 3D-QSAR model was evaluated for its predictive performance on a diverse test set containing 18 prostate cancer inhibitors. It presents very interesting internal and external statistical validation parameters (SD = 0.081;R2 = 0.903;Q2 = 0.869;;F = 247.2). This result suggests that the 3D-QSAR combinatorial model can be used to search for new 3VHE inhibitors and predict their potential activity. Based on the combinatorial pharmacophore model, a virtual screening of the Enamine database was performed. Compounds selected after virtual screening were subjected to molecular docking protocols (HTVS, SP, XP and IFD). Twenty new active compounds have been identified and their absorption, distribution, metabolism and excretion (ADME) property calculated using Schr?dinger’s Qikprop module. These results suggest that these new compounds could constitute new chemical starting points for further structural optimization of 3VHE inhibitors.
基金National Natural Science Foundation of China(Grant No.81373272)
文摘Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure ofα7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher＇s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.
文摘5-HT1A receptor is a crucial therapeutic target for the treatment of anxiety, depression, pain, etc. Design and preparation of potent 5-HT1A receptor ligands for drug discovery has attracted extensive attention in the past few years. In this paper, a three dimensional model of human 5-HT1A receptor was constructed by means of homology modeling. And the docking of MP349 to the receptor suggested a reliable binding mode for 5-HT1A receptor ligand. Based on this ligand-receptor binding mode, an elaborate receptor structure based pharmacophore model was established, which revealed many important features responsible for ligand and 5-HT1A receptor interactions. A virtual screening experiment verified the ability of this pharmacophore model to discover true 5-HT1A receptor ligand. The results of this research would provide important information for further optimizations of 5-HT1A receptor ligands and guide related new lead discoveries.
基金supported by the Research Special Fund for the National Great Science and Technology Projects(No.2012ZX09301002-001-001)the International Collaboration Project(No.2011DFR31240)Peking Union Medical College graduate student innovation fund(No.2013-1007-18)
文摘Naodesheng(NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease(AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target-biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods.
基金National Natural Science Foundation of China (Grant No. 30271538)985 program,Ministry of Education of China
文摘To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists.
基金supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.11KJB360004)the Jiangsu Provincial Natural Science Foundation of China(No.BK2012458),the National Natural Science Foundation of China(Nos.81373232,81173174,81270514)+1 种基金the National Key Technology R&D Program during the 11th Five-Year Plan Period(No.2008BAI51B02)the Doctoral Fund of Ministry of Education of China(No.20113237110008)
文摘Anticancer targets of cryptotanshinone were evaluated and rapidly forecasted with PharmMapper, a reverse pharmacophore-based screening platform, as well as drug target databases, including PDTD, DrugBank and TTD. The pathway analyses for the collection of anticancer targets screened were carried out based on the KEGG pathway database, followed by the forecast of potential pharmacological activities and pathways of the effects of cryptotanshinone, and verification of some of the targets screened using whole cell tests. The results showed that a total of eight targets with anticancer potential were screened, including MAP2K1, RARα, RXRα, PDK1, CHK1, AR, Ang-1 R, and Kif11. These targets are mainly related to four aspects of the cancer growth: the cell cycle, angiogenesis, apoptosis, and androgen receptor. The cell tests showed that cryptotanshinone can inhibit the viability of human hepatoma cells SMMC-7721, which is related to the reduction of expression of MAP2K1 mRNA. This method provides a strong clue for the study of the anticancer effects and mechanisms of action of cryptotanshinone in the future.
基金supported by the National Natural Science Foundation of China (No. 30472166)the Tianjin Commission of Science and Technology (06YFGZSH07000)
文摘The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.
基金The National Natural Science Foundation of China(Grant No.21272017 and 21572010)
文摘Multidrug resistance-associated proteins （MRPs） can effiux structurally diverse drugs, drug conjugates, drug metabolites, as well as other small molecules out of the cells, and this is the main cause of producing multidrug resistance （MDR） of some anticaneer drugs. Therefore, it is crucial to uncover the molecular features of MRPs substrates in developing anti-MDR cancer therapy. In the present study, common feature pharmacophore models were developed by employing CATALYST Pharmacophore Modeling and Analysis tools using substrates of MRPs, including MRP1, -2, -3, -4, -5, -6, -8 and MRPs family, respectively. The models were validated using independent decoy sets generated in DUD-E, and the ones with best A UC （area under the curve） scores were chosen to predict endogenous substrates by screening the Human Metabolome Database （HMDB）. A number of molecules obtained by pharmacophore screening have been validated in the literatures. By comparing physical properties （ALOGP, Molecular_PolarSurfaceArea, Molecular_Volume, Molecular_Weight, Num H Acceptors, Num H Donors） and scaffold features of the screened candidates with the known substrates, we found that： 1） The two sets have consistent ALOGP, Molecule_Volume and Molecule_Weight distribution trend; 2） Substrates of MRP1 have a better lipophilicity than the other subtypes, which is consistent with the two hydrophobic centers on the MRP1 pharmacophore; 3） In the aspect of the scaffold structures, they have the identical or similar backbone fragments.
基金Project supported by Department of Science and Technology,Govt.of India for Awarding Young Scientist Fellowship (SR/FT/LS-161/2008)
文摘The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.
文摘Cholesteryl ester transfer protein （CETP） is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol （HDL-C） levels and increasing low-density lipoprotein cholesterol （LDL-C） levels. Inhibition of CETP may be a new therapy for treating atherosclerosis. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H-10 as a potential CETP inhibitor in vitro. Based on H-10, a series of 3-（（3,4-dichlorophenyl）（4-substituted benzyl）amino） propanamides were designed, synthesized, and evaluated against CETP. Compound 41 was found to have the best activity, resulting in 85.0% inhibition of CETP at l0 μmol/L.
基金supported by the National Natural Science Foundation of China,No.20872095
文摘Fentanyl is a highly selective u-opioid receptor agonist with high analgesic activity. Three-dimensional pharmacophore models were built from a set of 50 fentanyl derivatives. These were employed to elucidate ligand-receptor interactions using information derived only from the ligand structure to identify new potential lead compounds. The present studies demonstrated that three hydrophobic regions, one positive ionizable region and two hydrogen bond acceptor region sites located on the molecule seem to be essential for analgesic activity. The results of the comparative molecular field analysis model suggested that both steric and electrostatic interactions play important roles. The contributions from steric and electrostatic fields for the model were 0.621 and 0.379, respectively. The pharmacophore model provides crucial information about how well the common features of a subject molecule overlap with the hypothesis model, which is very valuable for designing and optimizing new active structures.
基金National Science Foundation of China(Project No.81430094 and No.81603311)Beijing Municipal Natural Science Foundation(No.7164239).
文摘Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and clinical therapy.In this study,we investigated the relationship between transient receptor potential melastatin 8(TRPM8)and pungent flavor using three-dimensional pharmacophores based on virtual screening methods.Methods:Firstly,an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation.Then,several therapeutic targets,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoAR),cholesteryl ester transfer protein(CETP),Niemann-Pick C1-Like 1(NPC1L1)and platelet-activating factor receptor(PAFR),were selected to screen traditional Chinese herbs,and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets.Results:According to the screening results,TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8,which shares the common virtual screening hits with the therapeutic targets,was considered to be related to the action of pungent taste.Conclusion:The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.
文摘Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM) due to its non-insulin related characteristics with less side effects. Current commercially available hSGLT2 inhibitors are all C-glycoside inhibitors. Previous studies have reported that N-glycoside inhibitors have better potential to serve as new drugs due to their good metabolic stability. In addition, non-glycoside inhibitors have been shown to exhibit the capability to overcome the existing problems of current glycoside inhibitors, including low tissue permeability, poor stability and short serum half-time. Here, we aimed to discover novel N-glycoside and non-glycoside hSGLT2 inhibitors by a combination of several computational approaches. A ligand-based pharmacophore model was generated, well validated and subsequently utilized as a 3D query to identify novel hSGLT2 inhibitors from National Cancer Institute (NCI) and Traditional Chinese Medicine (TCM) databases. Finally, one N-glycoside (NSC679207) and one non-glycoside (TCM_Piperenol_A) hSGLT2 inhibitors were successfully identified, which were proven to exhibit excellent binding affinities, pharmacokinetic properties and less toxicity than the commercially available hSGLT2 inhibitor, canagliflozin, via molecular docking, ADMET prediction, molecular dynamics (MD) simulations and binding free energy calculations. All together, our results strongly suggest that these two compounds have great potential to serve as novel hSGLT2 inhibitors for the treatment of T2DM and their efficacies may be further examined by a series of in vitro and/or in vivo bioassays.
基金the National Key Research and Development Program of China(No.2021YFD1700100)National Natural Science Foundation of China(No.22007035,21837001)+1 种基金Knowledge Innovation Program of Wuhan-Basic Research(No.2022013301015174)the Key Research and Development Program of Hubei Province(2022BBA001).
文摘4-Hydroxyphenylpyruvate dioxygenase(EC 1.13.11.27,HPPD)is currently one of the popular targets of herbicide research,and herbicides targeting it have shown promising results in treating resistant weeds.However,the longterm application of HPPD inhibitors with in their classical scaffolds inevitably leads to the development of drug resistance.To further delay the underlying development of weed resistance to HPPD inhibitors,we successfully screened HPPD inhibitor pharmacophore with novel chelate structures using computer-aided drug molecular design and obtained 2-trifluoromethyltetrazolium nicotinamide derivatives through active fragment splicing.Among these derivatives,6-(3,3-diethyl-1-methylureido)-N-(1-methyl-1H-tetrazol-5-yl)-2-(trifluoromethyl)nicotinamide(compound 31),exhibited the most promising in vitro enzyme inhibitory activity,with IC_(50) value of 0.072μM,which was approximately five times better than that of the control agent mesotrione(IC_(50)?0.363μM).The crystal structure of the AtHPPD complexed with compound 31(2.0Å)and the binding energy calculations of the representative compounds revealed several important interactions of the ligand binding to the target protein,which explained the superior enzyme inhibitory activity of the compounds at the molecular level.In addition,compounds 7 and 31 possessed 100%inhibition against the five target weeds at the tested dosage and both were more effective against Setaria viridis than mesotrione.In general,it is promising to design novel HPPD inhibitors by developing novel chelating structures,and compounds 7 or 31 could be used as the leads for further development of valuable HPPD inhibitors.
基金The project supported by Hong Kong Baptist University(FRG2/12-13/021and FRG2/13-14/008)Centre for Cancer and Inflammation Research,School of Chinese Medicine(CCIR-SCM,HKBU)+5 种基金the Health and Medical Research Fund(HMRF/13121482)the Research Grants Council(HKBU/201811,HKBU/204612,and HKBU/201913)the French National Research Agency/Research Grants Council Joint Research Scheme(A-HKBU201/12)the Science and Technology Development Fund,Macao SAR(103/2012/A3)the University of Macao〔MYRG091(Y3-L2)-ICMS12-LCH,MYRG121(Y3-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS〕and University Research Committee Grant(RG55/06)from Nanyang Technological University and a Science and Engineering Research Council Grant(092 101 0053)from A*STAR,Singapore
文摘OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophore model from a set of TACE-selective inhibitor using the Common Feature Pharmacophore Model protocol implemented in Discovery Studio 3.1.1.A fluorimetric assay was used to investigate the potential ability of compounds to inhibit TACE enzymatic activity.The ability of compound 1 to inhibit TACE activity in a human monocyte THP-1 cell line was evaluated by ELISA.RESULTS In this study,apharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds,from which compound 1 emerged as a top candidate.In a cell-free assay,compound 1inhibited TACE enzymatic activity in a dose-dependent manner.Moreover,compound 1 inhibited the production of soluble TNF-αin human acute monocytic leukemia THP-1 cells without impacting nitric oxide production,and exhibited anti-proliferative activity against THP-1cells.CONCLUSION Compound 1 was found to inhibit TACE enzymatic activity in a cell-free system and LPS-induced TNF-αsecretion in cellulo.We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors.
