OBJECTIVE To apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90 000 natural product and natural product-like compounds.METHODS Molecular docking was used for the virtual screeni...OBJECTIVE To apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90 000 natural product and natural product-like compounds.METHODS Molecular docking was used for the virtual screening campaign and hit validation of STAT3 inhibitor.To further evaluate the potency of candidates at inhibiting STAT3-DNA binding activity,a STAT3 and STAT1transcription factor ELISA was performed.A dual-luciferase reporter assay,co-immunoprecipitation assay and Western blotting were carried out for the investigation of effect of compound 1 on STAT3-driven transcription,STAT3 dimerization and STAT3 phosphorylation.Finally,the cell toxicity of compound 1 was assessed by using MTT assay on different cell lines.RESULTS The virtual screening campaign furnished fourteen hit compounds,from which compound 1 emerged as a top candidate.Compound 1inhibited STAT3DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and comparable potency to the wellknown STAT3 inhibitor S3I-201.Furthermore,compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation.Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro.CONCLUSION The benzofuran derivative 1 was identified as a potential inhibitor of STAT3 dimerization using in silico screening.Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain.To the best of our knowledge,compound 1 has not been reported as a STAT3 inhibitor and no biological activity of compound 1 has been presented in the literature.展开更多
Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding ...Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.展开更多
Rosa roxburghii seeds are by-products of R.roxburghii processing,and their protein hydrolysates(RTSPHs)were found to possess a variety of biological activities.This study aimed to rapidly identify pancreatic lipase(PL...Rosa roxburghii seeds are by-products of R.roxburghii processing,and their protein hydrolysates(RTSPHs)were found to possess a variety of biological activities.This study aimed to rapidly identify pancreatic lipase(PL)and cholesterol esterase(CE)inhibitory peptides in RTSPHs and to elucidate their molecular mechanisms by combining peptidomics and virtual screening.The simulated intestinal environment worsened the peptide’s inhibition of PL but catalyzed the inhibition of CE.The fraction less than 3 kDa in RTSPHs was found to have the highest PL/CE inhibitory activity,among which 17 promising inhibitory peptides were identified and screened by peptidomics and virtual screening.LFCMH,RIPAGSPF,and YFRPR showed good inhibitory abilities against both PL and CE.Molecular docking showed that peptides inhibited PL and CE mainly by hydrogen bonding and hydrophobic interactions with residues in the active site and surface loop.Inhibition kinetic revealed that the peptides were competitive and mixed-type inhibitors of PL/CE.Further,the three peptides,LFCMH,RIPAGSPF,and YFRPR,could effectively inhibit 3T3-L1 preadipocytes differentiation,increase high-density lipoprotein cholesterol content and decrease low-density lipoprotein cholesterol content.This study suggests that combining peptidomics with virtual screening is an effective strategy for rapid screening of PL/CE inhibitory peptides.展开更多
Objective Immune infiltration and ferroptosis play pivotal roles in the progression of diabetic kidney disease(DKD).However,investigations of immune cell-related ferroptosis genes(ICRFGs)in the context of DKD are insu...Objective Immune infiltration and ferroptosis play pivotal roles in the progression of diabetic kidney disease(DKD).However,investigations of immune cell-related ferroptosis genes(ICRFGs)in the context of DKD are insufficient.This study aimed to identify ICRFGs relevant to DKD and screen related inhibitors.Methods In this study,two DKD datasets from the GEO database were utilized.We adopted the ESTIMATE algorithm to generate microenvironment scores.The CIBERSORT and WGCNA methods were employed to identify immune-related differentially expressed genes(DEGs).The common ICRFGs were derived through a Venn diagram.We employed random forest,LASSO,K-M survival,receiver operating characteristic(ROC)curve,clinical relevance,and Spearman correlation analyses to select hub ICRFGs further.Immunohistochemical experiments were also performed to validate the expression.Additionally,we utilized the Selleck database to obtain ferroptosis-related compounds and used USCF Chimera 1.14 to minimize energy,combined with molecular dynamics(MD)simulations to explore possible ferroptosis inhibitors.Results Immunohistochemical analysis revealed that arachidonate 5-lipoxygenase(ALOX5)was significantly highly expressed in the db/db group.Clinical correlation and K-M survival analyses confirmed ALOX5 as the most crucial ICRFG in DKD.Furthermore,ALOX5 was significantly enriched in the terms ECM-receptor interaction,regulation of chemokine production,and regulation of the inflammatory response.A positive correlation was observed between ALOX5 and M1 macrophages,γδT cells,and monocytes.Moreover,virtual screening and MD revealed NSC348884,salvianolic acid B,and deltarasin as potential ferroptosis inhibitors in combination with ALOX5.Conclusion We identified ALOX5 as a reliable and prospective diagnostic marker associated with immunity and ferroptosis in DKD patients.展开更多
The traditional nutritional and medical hemp(Cannabis sativa L.)seed protein were explored for the discovery and directional preparation of new xanthine oxidase inhibitory(XOI)peptides by structure-based virtual scree...The traditional nutritional and medical hemp(Cannabis sativa L.)seed protein were explored for the discovery and directional preparation of new xanthine oxidase inhibitory(XOI)peptides by structure-based virtual screening,compound synthesis,in vitro bioassay and proteolysis.Six subtypes of hemp seed edestin and albumin were in silico hydrolyzed by 29 proteases,and 192 encrypted bioactive peptides were screened out.Six peptides showed to be XOI peptides,of which four(about 67%)were released by elastase hydrolysis.The peptide DDNPRRFY displayed the highest XOI activity(IC50=(2.10±0.06)mg/mL),acting as a mixed inhibitor.The pancreatic elastase directionally prepared XOI hemp seed protein hydrolysates,from which 6 high-abundance XOI peptides encrypted 3 virtually-screened ones including the DDNPRRFY.The novel outstanding hemp seed protein-derived XOI peptides and their virtual screening and directed preparation methods provide a promising and applicable approach to conveniently and efficiently explore food-derived bioactive peptides.展开更多
Current biodegradation timelines show that polyesters take over 200 years to break down. A crucial component of several industries, polyesters are relied upon for materials development and thus require sustainable alt...Current biodegradation timelines show that polyesters take over 200 years to break down. A crucial component of several industries, polyesters are relied upon for materials development and thus require sustainable alternatives. Recent works in generative modeling have made it possible to produce large sets of chemical structures, but current molecular screening methods are expensive, not scalable, and are oversimplified. This work evaluates whether a molecule’s biodegradability potential can be accurately predicted by training a model on recent experimental data. Additionally, three chemical descriptors were evaluated on the final molecules for their effects on biodegradability: molecular structure, bond types, and solubility. A Gradient Boosted Machine was trained on a dataset of 600 molecules and their binary labels on biodegradability. The classification model effectively captured the biodegradability property, yielding an Area Under the Receiver Operating Characteristics, AUROC, of 84% and an Area Under the Precision Recall Curve, or AUPRC, of 87%. Additionally, an existing amortized synthetic tree generation model, SynNet, validated each molecule by showing chemical synthesizability and producing simple and interpretable synthesis pathways. This approach of filtering by prediction and chemical rule interpretation is inexpensive, highly scalable and can capture the necessary complexity. Using this method, novel polyester candidates can be polymerized and produced into sustainable fabrics, reducing environmental stress from textile-reliant industries.展开更多
Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes...Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes associated with this tumor. In this work, by targeting the 21-mer telomere G-quadruplex structure, compounds VB07 and VC02 were identified to stabilize the telomere G-quadruplex through structure-based high-throughput virtual screening. Cell cytotoxicity assay showed that VB07 and VC02 exhibited inhibitory effect on triple-negative breast cancer cells at the concentration of 5 μM. This study showed that structure-based high-throughput virtual screening was able to successfully identify the proper compounds targeting the telomere G-quadruplex, which exhibited inhibitory effects against the triple-negative breast cancer cells.展开更多
As a type II or III transmembrane glycoprotein, human CD38 is ubiquitously expressed in all mammalian tissues. CD38 is a multi-functional enzyme and a member of the ADP-ribosyl cyclase family, and it catalyzes nicotin...As a type II or III transmembrane glycoprotein, human CD38 is ubiquitously expressed in all mammalian tissues. CD38 is a multi-functional enzyme and a member of the ADP-ribosyl cyclase family, and it catalyzes nicotinamide adenine dinucleotide （NAD^＋） and nicotinamide adenine dinucleotide phosphate （NADP＋） to two distinct Ca^2＋ messengers as follows： cyclic ADP-ribose （cADPR） and nicotinic acid adenine dinucleotide phosphate （NAADP）, respectively. Moreover, both cADPR and NAADP mediate mobilization of intracellular Ca^2＋ targeting endoplasmic stores and the lysosomes, respectively. In this study, we combined ligand-based and structure-based virtual screening strategies to compare the inhibitor discovery efficacy based on natural substrates and the known inhibitors. The similarity queries towards SPECS database were carried out using ROCS and EON modules of OpenEye software. The hits were further docked to CD38 using AutoDock 4.05 program. In addition, ADME studies were also processed considering solubility in water and membrane permeability. Finally, we identified 17 compotmds-based on natural substrates and 10 compounds based on known inhibitor models. The results showed that the known inhibitor H2-based model was more efficient in virtual screening of CD38 non-covalent inhibitors.展开更多
Colonoscopy is the gold standard for the screening and diagnosis of colorectal cancer,resulting in a decrease in the incidence and mortality of colon cancer.However,it has a 21%rate of missed polyps.Several strategies...Colonoscopy is the gold standard for the screening and diagnosis of colorectal cancer,resulting in a decrease in the incidence and mortality of colon cancer.However,it has a 21%rate of missed polyps.Several strategies have been devised to increase polyp detection rates and improve their characterization and delimi-tation.These include chromoendoscopy(CE),the use of other devices such as Endo cuffs,and major advances in endoscopic equipment[high definition,magnification,narrow band imaging,i-scan,flexible spectral imaging color enhancement,texture and color enhancement imaging(TXI),etc.].In the retrospective study by Hiramatsu et al,they compared white-light imaging with CE,TXI,and CE+TXI to determine which of these strategies allows for better definition and delimitation of polyps.They concluded that employing CE associated with TXI stands out as the most effective method to utilize.It remains to be demonstrated whether these results are extrapolatable to other types of virtual CE.Additionally,further investigation is needed in order to ascertain whether this strategy could lead to a reduction in the recurrence of excised lesions and potentially lower the occurrence of interval cancer.展开更多
Angiotensin I converting enzyme （ACE） plays an important physiological role in the regulation of hypertension. In this study, we applied virtual screening to discover a novel angiotensin I converting enzyme inhibito...Angiotensin I converting enzyme （ACE） plays an important physiological role in the regulation of hypertension. In this study, we applied virtual screening to discover a novel angiotensin I converting enzyme inhibitory peptides from milk casein. One potential hit was identified based on docking scores, subsequently confirmed by activity studies in vitro （IC50=20.85 μmol L-1）. The proposed peptide in this study contains a unique sequence, Lys-Val-Leu-Ile-Leu-Ala. Moreover, we performed the docking studies to understand the binding mode between the enzyme and peptide hit.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
Finding energetic materials with tailored properties is always a significant challenge due to low research efficiency in trial and error.Herein,a methodology combining domain knowledge,a machine learning algorithm,and...Finding energetic materials with tailored properties is always a significant challenge due to low research efficiency in trial and error.Herein,a methodology combining domain knowledge,a machine learning algorithm,and experiments is presented for accelerating the discovery of novel energetic materials.A high-throughput virtual screening(HTVS)system integrating on-demand molecular generation and machine learning models covering the prediction of molecular properties and crystal packing mode scoring is established.With the proposed HTVS system,candidate molecules with promising properties and a desirable crystal packing mode are rapidly targeted from the generated molecular space containing 25112 molecules.Furthermore,a study of the crystal structure and properties shows that the good comprehensive performances of the target molecule are in agreement with the predicted results,thus verifying the effectiveness of the proposed methodology.This work demonstrates a new research paradigm for discovering novel energetic materials and can be extended to other organic materials without manifest obstacles.展开更多
The authors have created a virtual test of vibration particle-screening using Autodesk's 3ds Max software,the MAXScript scripting language and the AGEIA PhysX physics processing unit(PPU).The affect of various par...The authors have created a virtual test of vibration particle-screening using Autodesk's 3ds Max software,the MAXScript scripting language and the AGEIA PhysX physics processing unit(PPU).The affect of various parameters on screening efficiency were modeled.The parameters included vibration amplitude,frequency and direction.The length and inclination of the vibrating surface were also varied.The virtual experiment is in basic agreement with results predicted from screening theory.This shows that the virtual screener can be used for preliminary investigations and the results used to evaluate screen design.In addition it can help with theoretical research.展开更多
O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr...O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr） in proteins. Dysregulations of cellular O-GlcNAc have been implicated in diabetes, neurodegenerative disease, and cancer, which brings great interest in developing potent and specific small-molecular OGT inhibitors. In this work, we performed virtual screening on OGT catalytic site to identify potential inhibitors. 7134792 drug-like compounds from ZINC （a free database of commercially available compounds for virtual screening） and 4287550 compounds generated by FOG （fragment optimized growth program） were screened and the top 116 compounds ranked by docking score were analyzed. By comparing the screening results, we found FOG program can generate more compounds with better docking scores than ZINC. The top ZINC compounds ranked by docking score were grouped into two classes, which held the binding positions of UDP and GlcNAc of UDP- GlcNAc. Combined with individual fragments in binding pocket, de novo compounds were designed and proved to have better docking score. The screened and designed compounds may become a starting point for developing new drugs.展开更多
OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was em...OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of JAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in silico.The novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for JAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of 1a.The octyl(C8)analogue 1bdisplayed superior potency against JAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of JAK2.展开更多
The serotonin 2A（5-HT2A） receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a poten...The serotonin 2A（5-HT2A） receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of （593.89±34.10） nmol/L was discovered by integrating a set of computational approaches and experiments（protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay）.The 5-HT2A receptor showed a negatively charged bin-ding pocket.The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure,which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.展开更多
As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its developm...As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its development has attracted much attention. In the present study, we used four widely-used virtual screening programs to screen 7035 small molecules to identify potential L1 inhibitors, and a high-throughput experimental model of L1 inhibitors was established. In this high-throughput testing model, the inhibition rate of 163 compounds on L1 exceeded 40%. The results of virtual screening of 7035 small molecules using the following four programs showed that among the top 1.35% of the compounds, their hit rates were ranked as Schr?dinger’s(5.26%), DS(1.05%), and Sybyl-x 2.0(1.05%), and Smina(2.11%).展开更多
BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug des...BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug design（CADD）. Appropriate protein conformation and docking method are essential for the successful virtual screening experiments. One approach considering protein flexibility and multiple docking methods was proposed in this study. Six DFG-in/αC-helix-out crystal structures of BRAF, three docking programs（Glide, GOLD and Ligand Fit） and 12 scoring functions were applied for the best combination by judging from the results of pose prediction and retrospective virtual screening（VS）. The most accurate results（mean RMSD of about 0.6 A） of pose prediction were obtained with two complex structures（PDB： 3 C4 C and 3 SKC） using Glide SP. From the retrospective VS, the most active compounds were identified by using the complex structure of 3 SKC, indicated by a ROC/AUC score of 0.998 and an EF of 20.6 at 5% of the database screen with Glide-SP. On the whole, PDB 3 SKC could achieve a higher rate of correct reproduction, a better enrichment and more diverse compounds. A comparison of 3 SKC and the other X-ray crystal structures led to a rationale for the docking results. PDB 3 SKC could achieve a broad range of sulfonamide substitutions through an expanded hydrophobic pocket formed by a further shift of the αC-helix. Our study emphasized the necessity and significance of protein flexibility and scoring functions in both ligand docking and virtual screening.展开更多
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)+4 种基金the Health and Medical Research Fund(HMRF/13121482)the Research Grants Council(HKBU/201811,HKBU/204612and 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/A3,001/2012/A)the University of Macao〔MYRG091(Y3-L2)-ICMS12-LCH,MYRG121(Y3-L2)-ICMS12-LCH,MRG007/LCH/2014/ICMS and MRG023/LCH/2013/ICMS〕
文摘OBJECTIVE To apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90 000 natural product and natural product-like compounds.METHODS Molecular docking was used for the virtual screening campaign and hit validation of STAT3 inhibitor.To further evaluate the potency of candidates at inhibiting STAT3-DNA binding activity,a STAT3 and STAT1transcription factor ELISA was performed.A dual-luciferase reporter assay,co-immunoprecipitation assay and Western blotting were carried out for the investigation of effect of compound 1 on STAT3-driven transcription,STAT3 dimerization and STAT3 phosphorylation.Finally,the cell toxicity of compound 1 was assessed by using MTT assay on different cell lines.RESULTS The virtual screening campaign furnished fourteen hit compounds,from which compound 1 emerged as a top candidate.Compound 1inhibited STAT3DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and comparable potency to the wellknown STAT3 inhibitor S3I-201.Furthermore,compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation.Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro.CONCLUSION The benzofuran derivative 1 was identified as a potential inhibitor of STAT3 dimerization using in silico screening.Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain.To the best of our knowledge,compound 1 has not been reported as a STAT3 inhibitor and no biological activity of compound 1 has been presented in the literature.
基金supported by the National Key R&D Program of China (Grant Nos.2016YFA0501701 and 2016YFA0202900)the National Natural Science Foundation of China (Grant Nos.21575128,81773632,and 81302679)
文摘Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
基金supported by Yunnan Fundamental Research Project(202301AS070014)Science and Technology Plan Project in Guizhou Province([2020]1Y022).
文摘Rosa roxburghii seeds are by-products of R.roxburghii processing,and their protein hydrolysates(RTSPHs)were found to possess a variety of biological activities.This study aimed to rapidly identify pancreatic lipase(PL)and cholesterol esterase(CE)inhibitory peptides in RTSPHs and to elucidate their molecular mechanisms by combining peptidomics and virtual screening.The simulated intestinal environment worsened the peptide’s inhibition of PL but catalyzed the inhibition of CE.The fraction less than 3 kDa in RTSPHs was found to have the highest PL/CE inhibitory activity,among which 17 promising inhibitory peptides were identified and screened by peptidomics and virtual screening.LFCMH,RIPAGSPF,and YFRPR showed good inhibitory abilities against both PL and CE.Molecular docking showed that peptides inhibited PL and CE mainly by hydrogen bonding and hydrophobic interactions with residues in the active site and surface loop.Inhibition kinetic revealed that the peptides were competitive and mixed-type inhibitors of PL/CE.Further,the three peptides,LFCMH,RIPAGSPF,and YFRPR,could effectively inhibit 3T3-L1 preadipocytes differentiation,increase high-density lipoprotein cholesterol content and decrease low-density lipoprotein cholesterol content.This study suggests that combining peptidomics with virtual screening is an effective strategy for rapid screening of PL/CE inhibitory peptides.
基金supported by the Guizhou Provincial Basic Research Program(Natural Science)(No.Qiankehe Foundation-ZK[2023]General 428)Guizhou Provincial Department of Education 2024 Natural Science Research Project(Youth Science and Technology Talent Growth Project)(No.Qiankejiao[2024]116)the Science and Technology Foundation of Guizhou Provincial Health Commission(No.gzwkj2022-008).
文摘Objective Immune infiltration and ferroptosis play pivotal roles in the progression of diabetic kidney disease(DKD).However,investigations of immune cell-related ferroptosis genes(ICRFGs)in the context of DKD are insufficient.This study aimed to identify ICRFGs relevant to DKD and screen related inhibitors.Methods In this study,two DKD datasets from the GEO database were utilized.We adopted the ESTIMATE algorithm to generate microenvironment scores.The CIBERSORT and WGCNA methods were employed to identify immune-related differentially expressed genes(DEGs).The common ICRFGs were derived through a Venn diagram.We employed random forest,LASSO,K-M survival,receiver operating characteristic(ROC)curve,clinical relevance,and Spearman correlation analyses to select hub ICRFGs further.Immunohistochemical experiments were also performed to validate the expression.Additionally,we utilized the Selleck database to obtain ferroptosis-related compounds and used USCF Chimera 1.14 to minimize energy,combined with molecular dynamics(MD)simulations to explore possible ferroptosis inhibitors.Results Immunohistochemical analysis revealed that arachidonate 5-lipoxygenase(ALOX5)was significantly highly expressed in the db/db group.Clinical correlation and K-M survival analyses confirmed ALOX5 as the most crucial ICRFG in DKD.Furthermore,ALOX5 was significantly enriched in the terms ECM-receptor interaction,regulation of chemokine production,and regulation of the inflammatory response.A positive correlation was observed between ALOX5 and M1 macrophages,γδT cells,and monocytes.Moreover,virtual screening and MD revealed NSC348884,salvianolic acid B,and deltarasin as potential ferroptosis inhibitors in combination with ALOX5.Conclusion We identified ALOX5 as a reliable and prospective diagnostic marker associated with immunity and ferroptosis in DKD patients.
基金funded by National Natural Science Foundation of China(21868003)Bama County Program for Talents in Science and Technology(BaRenKe20210045).
文摘The traditional nutritional and medical hemp(Cannabis sativa L.)seed protein were explored for the discovery and directional preparation of new xanthine oxidase inhibitory(XOI)peptides by structure-based virtual screening,compound synthesis,in vitro bioassay and proteolysis.Six subtypes of hemp seed edestin and albumin were in silico hydrolyzed by 29 proteases,and 192 encrypted bioactive peptides were screened out.Six peptides showed to be XOI peptides,of which four(about 67%)were released by elastase hydrolysis.The peptide DDNPRRFY displayed the highest XOI activity(IC50=(2.10±0.06)mg/mL),acting as a mixed inhibitor.The pancreatic elastase directionally prepared XOI hemp seed protein hydrolysates,from which 6 high-abundance XOI peptides encrypted 3 virtually-screened ones including the DDNPRRFY.The novel outstanding hemp seed protein-derived XOI peptides and their virtual screening and directed preparation methods provide a promising and applicable approach to conveniently and efficiently explore food-derived bioactive peptides.
文摘Current biodegradation timelines show that polyesters take over 200 years to break down. A crucial component of several industries, polyesters are relied upon for materials development and thus require sustainable alternatives. Recent works in generative modeling have made it possible to produce large sets of chemical structures, but current molecular screening methods are expensive, not scalable, and are oversimplified. This work evaluates whether a molecule’s biodegradability potential can be accurately predicted by training a model on recent experimental data. Additionally, three chemical descriptors were evaluated on the final molecules for their effects on biodegradability: molecular structure, bond types, and solubility. A Gradient Boosted Machine was trained on a dataset of 600 molecules and their binary labels on biodegradability. The classification model effectively captured the biodegradability property, yielding an Area Under the Receiver Operating Characteristics, AUROC, of 84% and an Area Under the Precision Recall Curve, or AUPRC, of 87%. Additionally, an existing amortized synthetic tree generation model, SynNet, validated each molecule by showing chemical synthesizability and producing simple and interpretable synthesis pathways. This approach of filtering by prediction and chemical rule interpretation is inexpensive, highly scalable and can capture the necessary complexity. Using this method, novel polyester candidates can be polymerized and produced into sustainable fabrics, reducing environmental stress from textile-reliant industries.
基金National Natural Science Foundation of China(Grant No.31701791,21732002,31672558 and 21502060)Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(Grant No.2662017PY113,2015RC013 and 2662015PY208)Open fund of The State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS(Grant No.SKLBNPC16343)。
文摘Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes associated with this tumor. In this work, by targeting the 21-mer telomere G-quadruplex structure, compounds VB07 and VC02 were identified to stabilize the telomere G-quadruplex through structure-based high-throughput virtual screening. Cell cytotoxicity assay showed that VB07 and VC02 exhibited inhibitory effect on triple-negative breast cancer cells at the concentration of 5 μM. This study showed that structure-based high-throughput virtual screening was able to successfully identify the proper compounds targeting the telomere G-quadruplex, which exhibited inhibitory effects against the triple-negative breast cancer cells.
基金National Natural Science Foundation of China(Grant No.21272017 and 81172917)
文摘As a type II or III transmembrane glycoprotein, human CD38 is ubiquitously expressed in all mammalian tissues. CD38 is a multi-functional enzyme and a member of the ADP-ribosyl cyclase family, and it catalyzes nicotinamide adenine dinucleotide （NAD^＋） and nicotinamide adenine dinucleotide phosphate （NADP＋） to two distinct Ca^2＋ messengers as follows： cyclic ADP-ribose （cADPR） and nicotinic acid adenine dinucleotide phosphate （NAADP）, respectively. Moreover, both cADPR and NAADP mediate mobilization of intracellular Ca^2＋ targeting endoplasmic stores and the lysosomes, respectively. In this study, we combined ligand-based and structure-based virtual screening strategies to compare the inhibitor discovery efficacy based on natural substrates and the known inhibitors. The similarity queries towards SPECS database were carried out using ROCS and EON modules of OpenEye software. The hits were further docked to CD38 using AutoDock 4.05 program. In addition, ADME studies were also processed considering solubility in water and membrane permeability. Finally, we identified 17 compotmds-based on natural substrates and 10 compounds based on known inhibitor models. The results showed that the known inhibitor H2-based model was more efficient in virtual screening of CD38 non-covalent inhibitors.
文摘Colonoscopy is the gold standard for the screening and diagnosis of colorectal cancer,resulting in a decrease in the incidence and mortality of colon cancer.However,it has a 21%rate of missed polyps.Several strategies have been devised to increase polyp detection rates and improve their characterization and delimi-tation.These include chromoendoscopy(CE),the use of other devices such as Endo cuffs,and major advances in endoscopic equipment[high definition,magnification,narrow band imaging,i-scan,flexible spectral imaging color enhancement,texture and color enhancement imaging(TXI),etc.].In the retrospective study by Hiramatsu et al,they compared white-light imaging with CE,TXI,and CE+TXI to determine which of these strategies allows for better definition and delimitation of polyps.They concluded that employing CE associated with TXI stands out as the most effective method to utilize.It remains to be demonstrated whether these results are extrapolatable to other types of virtual CE.Additionally,further investigation is needed in order to ascertain whether this strategy could lead to a reduction in the recurrence of excised lesions and potentially lower the occurrence of interval cancer.
基金supported by the National High Technology Research and Development Program of China(863 Program, 2008AA10Z313)the Foundation for Sciand Tech Research Project of Zhejiang Province, China(2006C12096)Natural Science Foundation of Zhejiang Province, China (Y3090026)
文摘Angiotensin I converting enzyme （ACE） plays an important physiological role in the regulation of hypertension. In this study, we applied virtual screening to discover a novel angiotensin I converting enzyme inhibitory peptides from milk casein. One potential hit was identified based on docking scores, subsequently confirmed by activity studies in vitro （IC50=20.85 μmol L-1）. The proposed peptide in this study contains a unique sequence, Lys-Val-Leu-Ile-Leu-Ala. Moreover, we performed the docking studies to understand the binding mode between the enzyme and peptide hit.
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the Science Challenge Project(TZ2018004)the National Natural Science Foundation of China(21875228 and 21702195)for financial support。
文摘Finding energetic materials with tailored properties is always a significant challenge due to low research efficiency in trial and error.Herein,a methodology combining domain knowledge,a machine learning algorithm,and experiments is presented for accelerating the discovery of novel energetic materials.A high-throughput virtual screening(HTVS)system integrating on-demand molecular generation and machine learning models covering the prediction of molecular properties and crystal packing mode scoring is established.With the proposed HTVS system,candidate molecules with promising properties and a desirable crystal packing mode are rapidly targeted from the generated molecular space containing 25112 molecules.Furthermore,a study of the crystal structure and properties shows that the good comprehensive performances of the target molecule are in agreement with the predicted results,thus verifying the effectiveness of the proposed methodology.This work demonstrates a new research paradigm for discovering novel energetic materials and can be extended to other organic materials without manifest obstacles.
基金Projects 50574091 and 50774084 supported by the National Natural Science Foundation of China
文摘The authors have created a virtual test of vibration particle-screening using Autodesk's 3ds Max software,the MAXScript scripting language and the AGEIA PhysX physics processing unit(PPU).The affect of various parameters on screening efficiency were modeled.The parameters included vibration amplitude,frequency and direction.The length and inclination of the vibrating surface were also varied.The virtual experiment is in basic agreement with results predicted from screening theory.This shows that the virtual screener can be used for preliminary investigations and the results used to evaluate screen design.In addition it can help with theoretical research.
文摘O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr） in proteins. Dysregulations of cellular O-GlcNAc have been implicated in diabetes, neurodegenerative disease, and cancer, which brings great interest in developing potent and specific small-molecular OGT inhibitors. In this work, we performed virtual screening on OGT catalytic site to identify potential inhibitors. 7134792 drug-like compounds from ZINC （a free database of commercially available compounds for virtual screening） and 4287550 compounds generated by FOG （fragment optimized growth program） were screened and the top 116 compounds ranked by docking score were analyzed. By comparing the screening results, we found FOG program can generate more compounds with better docking scores than ZINC. The top ZINC compounds ranked by docking score were grouped into two classes, which held the binding positions of UDP and GlcNAc of UDP- GlcNAc. Combined with individual fragments in binding pocket, de novo compounds were designed and proved to have better docking score. The screened and designed compounds may become a starting point for developing new drugs.
基金The project upported 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)+4 种基金the Health and Medical Research Fund(HMRF/11101212and HMRF/13121482)the Research Grants Council(HKBU/201811,HKBU/204612and HKBU/201913)the French National Research Agency/Research Grants Council Joint Research Scheme(A-HKBU201/12)the State Key Laboratory of Synthetic Chemistry,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,MRG007/LCH/2014/ICMS and MRG023/LCH/2013/ICMS〕
文摘OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of JAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in silico.The novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for JAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of 1a.The octyl(C8)analogue 1bdisplayed superior potency against JAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of JAK2.
基金Supported by the National High Technology Research and Development Program of China(No.2009AA02Z308)the Major State Basic Research Development Program of China(No.2010CB912601)the National Natural Science Foundation of China (No.20702009)
文摘The serotonin 2A（5-HT2A） receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of （593.89±34.10） nmol/L was discovered by integrating a set of computational approaches and experiments（protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay）.The 5-HT2A receptor showed a negatively charged bin-ding pocket.The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure,which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.
基金Natural Sciences Foundation of China (Grant No. 81872913)National High-tech R&D Program (863 Program, Grant No. 2015AA020911)。
文摘As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its development has attracted much attention. In the present study, we used four widely-used virtual screening programs to screen 7035 small molecules to identify potential L1 inhibitors, and a high-throughput experimental model of L1 inhibitors was established. In this high-throughput testing model, the inhibition rate of 163 compounds on L1 exceeded 40%. The results of virtual screening of 7035 small molecules using the following four programs showed that among the top 1.35% of the compounds, their hit rates were ranked as Schr?dinger’s(5.26%), DS(1.05%), and Sybyl-x 2.0(1.05%), and Smina(2.11%).
基金supported by the National Natural Science Foundation of China(21102181,81302634 and 21572273)
文摘BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug design（CADD）. Appropriate protein conformation and docking method are essential for the successful virtual screening experiments. One approach considering protein flexibility and multiple docking methods was proposed in this study. Six DFG-in/αC-helix-out crystal structures of BRAF, three docking programs（Glide, GOLD and Ligand Fit） and 12 scoring functions were applied for the best combination by judging from the results of pose prediction and retrospective virtual screening（VS）. The most accurate results（mean RMSD of about 0.6 A） of pose prediction were obtained with two complex structures（PDB： 3 C4 C and 3 SKC） using Glide SP. From the retrospective VS, the most active compounds were identified by using the complex structure of 3 SKC, indicated by a ROC/AUC score of 0.998 and an EF of 20.6 at 5% of the database screen with Glide-SP. On the whole, PDB 3 SKC could achieve a higher rate of correct reproduction, a better enrichment and more diverse compounds. A comparison of 3 SKC and the other X-ray crystal structures led to a rationale for the docking results. PDB 3 SKC could achieve a broad range of sulfonamide substitutions through an expanded hydrophobic pocket formed by a further shift of the αC-helix. Our study emphasized the necessity and significance of protein flexibility and scoring functions in both ligand docking and virtual screening.
