Computer-aided drug design (CADD) is an interdisciplinary subject, playing a pivotal role during new drug research and development, especially the discovery and optimization of lead compounds. Traditional Chinese Medi...Computer-aided drug design (CADD) is an interdisciplinary subject, playing a pivotal role during new drug research and development, especially the discovery and optimization of lead compounds. Traditional Chinese Medicine (TCM) modernization is the only way of TCM development and also an effective approach to the development of new drugs and the discovery of potential drug targets (PDTs). Discovery and validation of PTDs has become the “bottle-neck” restricted new drug research and development and is urgently solved. Innovative drug research is of great significance and bright prospects. This paper mainly discusses the “druggability” and specificity of PTDs, the “druglikeness” of drug candidates, the methods and technologies of the discovery and validation of PTDs and their application. It is very important to achieve the invention and innovation strategy “from gene to drug”. In virtue of modern high-new technology, especially CADD, combined with TCM theory, research and develop TCM and initiate an innovating way fitting our country progress. This paper mainly discusses CADD and their application to drug research, especially TCM modernization.展开更多
Dental caries,a chronic disease characterized by tooth decay,occupies the second position in terms of disease burden and is primarily caused by cariogenic bacteria,especially Streptococcus mutans,because of its acidog...Dental caries,a chronic disease characterized by tooth decay,occupies the second position in terms of disease burden and is primarily caused by cariogenic bacteria,especially Streptococcus mutans,because of its acidogenic,aciduric,and biofilm-forming capabilities.Developing novel targeted anti-virulence agents is always a focal point in caries control to overcome the limitations of conventional anti-virulence agents.The current study represents an up-to-date review of in silico approaches of drug design against dental caries,which have emerged more and more powerful complementary to biochemical attempts.Firstly,we categorize the in silico approaches into computer-aided drug design(CADD)and AI-assisted drug design(AIDD)and highlight the specific methods and models they contain respectively.Subsequently,we detail the design of anti-virulence drugs targeting single or multiple cariogenic virulence targets of S.mutans,such as glucosyltransferases(Gtfs),antigen I/II(AgI/II),sortase A(SrtA),the VicRK signal transduction system and superoxide dismutases(SODs).Finally,we outline the current opportunities and challenges encountered in this field to aid future endeavors and applications of CADD and AIDD in anti-virulence drug design.展开更多
The evolution of cancer therapies has highlighted the limitations of traditional chemotherapy,particularly its lack of specificity and off-target toxicities,driving the development of targeted treatments like small mo...The evolution of cancer therapies has highlighted the limitations of traditional chemotherapy,particularly its lack of specificity and off-target toxicities,driving the development of targeted treatments like small molecule-drug conjugates(SMDCs).SMDCs offer distinct advantages over antibody-drug conjugates(ADCs),including simpler synthesis,lower production costs,and improved solid tumor penetration due to their smaller size.However,challenges remain,such as a limited variety of targeting ligands and the complexity of optimizing selectivity and efficacy within the tumor microenvironment.This review focuses on key aspects such as mechanisms of action,biomarker selection,and the optimization of each component of SMDCs.It also covers SMDCs that have been approved or are currently under active clinical trials,while providing insights into future developments in this promising field of targeted cancer therapies.展开更多
In the year 1971,the world’s biggest structural biology collaboration name—The Research Collaboratory for Structural Bioinformatics(RCSB),was formed to gather all the structural biologists at a single platform and t...In the year 1971,the world’s biggest structural biology collaboration name—The Research Collaboratory for Structural Bioinformatics(RCSB),was formed to gather all the structural biologists at a single platform and then extended out to be the world’s most extensive structural data repository named RCSB-Protein Data Bank(PDB)(https://www.rcsb.org/)that has provided the service for more than 50 years and continues its legacy for the discoveries and repositories for structural data.The RCSB has evolved from being a collaboratory network to a full-fledged database and tool with a huge list of protein structures,nucleic acid-containing structures,ModelArchive,and AlphaFold structures,and the best is that it is expanding day by day with computational advancement with tools and visual experiences.In this review article,we have discussed how RCSB has been a successful collaboratory network,its expansion in each decade,and how it has helped the ground-breaking research.The PDB tools that are helping the researchers,yearly data deposition,validation,processing,and suggestions that can help the developer improve for upcoming years are also discussed.This review will help future researchers understand the complete history of RCSB and its developments in each decade and how various future collaborative networks can be developed in various scientific areas and can be successful by keeping RCSB as a case study.展开更多
Due to the practical problems of the high costs and the long development cycle of China’s cabinet production,a computer-aided design method of the cabinet based on style imagery is proposed.According to the principle...Due to the practical problems of the high costs and the long development cycle of China’s cabinet production,a computer-aided design method of the cabinet based on style imagery is proposed.According to the principle of the conjoint analysis method, the rough set theory and the weight coefficient of different components of the cabinet,a multi-dimensional model of style imagery to evaluate the cabinet is built. Then the related constants of style imagery are calculated and the cabinet components library is also built by the three-dimensional modeling.Finally,with recombinant technology and the mapping model between cabinet style and external characteristics,the prototype system based on Visual Studio is proposed.This system actualizes the bidirectional reasoning between product style imagery and the shape features,which can assist designers to produce more creative designs,greatly improve the efficiency of cabinet development and increase the profits of companies.展开更多
Attributing to their broad pharmacological effects encompassing anti-inflammation,antitoxin,and immunosuppression,glucocorticoids(GCs)are extensively utilized in the clinic for the treatment of diverse diseases such a...Attributing to their broad pharmacological effects encompassing anti-inflammation,antitoxin,and immunosuppression,glucocorticoids(GCs)are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus,nephritis,arthritis,ulcerative colitis,asthma,keratitis,macular edema,and leukemia.However,longterm use often causes undesirable side effects,including metabolic disorders-induced Cushing's syndrome(buffalo back,full moon face,hyperglycemia,etc.),osteoporosis,aggravated infection,psychosis,glaucoma,and cataract.These notorious side effects seriously compromise patients'quality of life,especially in patients with chronic diseases.Therefore,glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention.Among them,prodrugs have the advantages of low investment,low risk,and high success rate,making them a promising strategy.In this review,we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades,including polymer-based prodrugs,dendrimer-based prodrugs,antibody-drug conjugates,peptide-drug conjugates,carbohydrate-based prodrugs,aliphatic acid-based prodrugs and so on.Besides,we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs.This review is expected to be helpful for the research and development of novel GCs and prodrugs.展开更多
The finite element analysis and the optimum design of aluminum profile extrusion mould were investigated using the ANSYS software and its parameterized modeling method. The optimum dimensions of the mould were obtaine...The finite element analysis and the optimum design of aluminum profile extrusion mould were investigated using the ANSYS software and its parameterized modeling method. The optimum dimensions of the mould were obtained. It is found that the stress distribution is very uneven, and the stress convergence is rather severe in the bridge of the aluminum profile extrusion mould. The optimum height of the mould is 70.527 mm, and the optimum radius of dividing holes are 70.182 mm and 80.663 mm. Increasing the height of the mould in the range of 61.282 mm to 70.422 mm can prolong its longevity, but when the height is over 70.422 mm, its longevity reduces.展开更多
Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate vario...Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.展开更多
Thermodynamic and kinetic study on TRIP （transformation induced plasticity） steels, cemented carbides and mold steel for plastics were carried out in order to design modern advanced materials. With the sublattice mo...Thermodynamic and kinetic study on TRIP （transformation induced plasticity） steels, cemented carbides and mold steel for plastics were carried out in order to design modern advanced materials. With the sublattice model, equilibrium compositions of ferrite and austenite phases in TRIP steels, as well as volume fraction of austenite at inter-critical temperatures for different time were calculated. Concentration profiles of carbon, manganese, aluminum and silicon in the steels were also estimated in the lattice fixed frame of reference. The effect of Si and Mn on TRIP was discussed according to thermodynamic and kinetic analyses. In order to understand and produce the graded nanophase structure of cemented carbides, miscellaneous phases in the M-Co-C （M= Ti, Ta, Nh） systems and Co-V-C system were modeled. Solution parameters and thermodynamic： properties were listed in detail. The improvement of machining behavior of prehardened mould steel for plastics was obtained by computer-aided composition design. The results showed that the matrix composition of large-section prehardened mould steel for plastic markedly influences the precipitation of non-metallic inclusion and the composition control by the aid of Thermo-Calc software package minimizes the amount of detrimental oxide inclusion. In addition, the modification of calcium was optimized in composition design.展开更多
Suitable optimization and simulation were performed using a powerful software package with a mature database as well as modem measurement facilities, which led to the successful designing and manufacturing of advanced...Suitable optimization and simulation were performed using a powerful software package with a mature database as well as modem measurement facilities, which led to the successful designing and manufacturing of advanced steels. In the course of designing, the composition of a large section of prehardened mold steel for plastics was estimated so as to lower the quantities of oxide inclusions to change the type of carbides and to raise the machinability. The composition and process were adjusted to obtain satisfactory surface quality for the prevailing galvanization in transformation-induced plasticity （TRIP） steel. The refuting process of low-carbon steel was simulated in the light of both Thermo-Calc and Factsage. Thermodynamic and kinetic analyses were always conducted during the test and the procedure.展开更多
The general computer-aided design （CAD） software cannot meet the mould design requirement of the autoclave process for composites, because many parameters such as temperature and pressure should be considered in the...The general computer-aided design （CAD） software cannot meet the mould design requirement of the autoclave process for composites, because many parameters such as temperature and pressure should be considered in the mould design process, in addition to the material and geometry of the part. A framed-mould computer-aided design system （FMCAD） used in the autoclave moulding process is proposed in this paper. A function model of the software is presented, in which influence factors such as part structure, mould structure, and process parameters are considered; a design model of the software is established using object oriented （O-O） technology to integrate the stiffness calculation, temperature field calculation, and deformation field calculation of mould in the design, and in the design model, a hybrid model of mould based on calculation feature and form feature is presented to support those calculations. A prototype system is developed, in which a mould design process wizard is built to integrate the input information, calculation, analysis, data storage, display, and design results of mould design. Finally, three design examples are used to verify the prototype.展开更多
Fully human antibodies have minimal immunogenicity and safety profiles.At present,most potential antibody drugs in clinical trials are humanized or fully human.Human antibodies are mostly generated using the phage dis...Fully human antibodies have minimal immunogenicity and safety profiles.At present,most potential antibody drugs in clinical trials are humanized or fully human.Human antibodies are mostly generated using the phage display method(in vitro)or by transgenic mice(in vivo);other methods include B lymphocyte immortalization,human–human hybridoma,and single-cell polymerase chain reaction.Here,we describe a structure-based computer-aided de novo design technology for human antibody generation.Based on the complex structure of human epidermal growth factor receptor 2(HER2)/Herceptin,we first designed six short peptides targeting the potential epitope of HER2 recognized by Herceptin.Next,these peptides were set as complementarity determining regions in a suitable immunoglobulin frame,giving birth to a novel anti-HER2 antibody named "HF,"which possessed higher affinity and more effective anti-tumor activity than Herceptin.Our work offers a useful tool for the quick design and selection of novel human antibodies for basic mechanical research as well as for imaging and clinical applications in immune-related diseases,such as cancer and infectious diseases.展开更多
Because of the powerful mapping ability, back propagation neural network (BP-NN) has been employed in computer-aided product design (CAPD) to establish the property prediction model. The backward problem in CAPD is to...Because of the powerful mapping ability, back propagation neural network (BP-NN) has been employed in computer-aided product design (CAPD) to establish the property prediction model. The backward problem in CAPD is to search for the appropriate structure or composition of the product with desired property, which is an optimization problem. In this paper, a global optimization method of using the a BB algorithm to solve the backward problem is presented. In particular, a convex lower bounding function is constructed for the objective function formulated with BP-NN model, and the calculation of the key parameter a is implemented by recurring to the interval Hessian matrix of the objective function. Two case studies involving the design of dopamine β-hydroxylase (DβH) inhibitors and linear low density polyethylene (LLDPE) nano composites are investigated using the proposed method.展开更多
Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the...Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data,these models showcase remarkable efficacy across various tasks,including new drug design and drug target identification.The adaptability of pre-trained trans-former-based models renders them indispensable assets for driving data-centric advancements in drug discovery,chemistry,and biology,furnishing a robust framework that expedites innovation and dis-covery within these domains.Beyond their technical prowess,the success of transformer-based models in drug discovery,chemistry,and biology extends to their interdisciplinary potential,seamlessly combining biological,physical,chemical,and pharmacological insights to bridge gaps across diverse disciplines.This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields.In our review,we elucidate the myriad applications of transformers in drug discovery,as well as chemistry and biology,spanning from protein design and protein engineering,to molecular dynamics(MD),drug target iden-tification,transformer-enabled drug virtual screening(VS),drug lead optimization,drug addiction,small data set challenges,chemical and biological image analysis,chemical language understanding,and single cell data.Finally,we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.展开更多
Custom-made esthetic finger prostheses, which are used for rehabilitation of patients with missing or impaired fingers, have been fabricated manually. However, such fabrication is time-consuming and requires manual sk...Custom-made esthetic finger prostheses, which are used for rehabilitation of patients with missing or impaired fingers, have been fabricated manually. However, such fabrication is time-consuming and requires manual skill. Here we propose a computer-aided method for fabricating finger pros-theses to save time and allow fabrications that do not require considerable manual skill. In this method, the dimensions of a patient’s healthy finger on the contralateral hand are first measured using a caliper. Using these dimensions, a three-dimensional model is constructed for fabricating a prosthesis for the patient’s impaired finger. Using the 3D model, a mold is designed using 3D modeling tools and a computer-aided design system. The resulting mold is then fabricated using a 3D printer. A finger prosthesis is fabricated by pouring silicone resin into the mold. A finger prosthesis for a volunteer was experimentally fabricated according to the proposed method. To evaluate the size and shape of the finger prosthesis, the difference between the finger prosthesis and the original finger of the volunteer was analyzed. Because the average difference between them was 0.25 mm, it was concluded that the proposed method could be used to fabricate a finger prosthesis of adequate size and shape.展开更多
The article is to study the development of computer-aided design of X-ray microtomography—the device for investigating the structure and construction of three-dimensional images of organic and inorganic objects on th...The article is to study the development of computer-aided design of X-ray microtomography—the device for investigating the structure and construction of three-dimensional images of organic and inorganic objects on the basis of shadow projections. This article provides basic information regarding CAD of X-ray microtomography and a scheme consisting of three levels. The article also shows basic relations of X-ray computed tomography, the generalized scheme of an X-ray microtomographic scanner. The methods of X-ray imaging of the spatial microstructure and morphometry of materials are described. The main characteristics of an X-ray microtomographic scanner, the X-ray source, X-ray optical elements and mechanical components of the positioning system are shown. The block scheme and software functional scheme for intelligent neural network system of analysis of the internal microstructure of objects are presented. The method of choice of design parameters of CAD of X-ray microtomography aims at improving the quality of design and reducing costs of it. It is supposed to reduce the design time and eliminate the growing number of engineers involved in development and construction of X-ray microtomographic scanners.展开更多
In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light o...In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.展开更多
Introduction Since the 21st century,the biomedical field has gained increasing attention.The biomedical field mainly encompasses biology,materials science,pharmacology,and drug delivery,etc.These areas hold significan...Introduction Since the 21st century,the biomedical field has gained increasing attention.The biomedical field mainly encompasses biology,materials science,pharmacology,and drug delivery,etc.These areas hold significant importance for human society in terms of health protection,disease diagnosis and treatment,via medical technology innovation and drug development.Consequently,scientists place great emphasis on research in this domain.It must be noted that the research process in biomedicine mainly includes topic selection,experimentation,analysis,and summary.Among these,topic selection is a critical step that affects the entire process.This topic selection not only clarifies the direction and objectives of the study but also provides a clear framework for subsequent research,thereby ensuring scientific rigor and effectiveness while laying a solid foundation for the result analysis.Thus,how to approach topic selection is a crucial issue that requires careful consideration.展开更多
In 2024,the U.S.Food and Drug Administration approved a total of 50 drug marketing applications,with small molecule drugs accounting for half of the medications.Upon surveying these endorsed pharmaceuticals,it becomes...In 2024,the U.S.Food and Drug Administration approved a total of 50 drug marketing applications,with small molecule drugs accounting for half of the medications.Upon surveying these endorsed pharmaceuticals,it becomes evident that certain structures exhibit familiarity,potentially resulting from structural modifications applied to previously approved drugs.Consequently,exploring the latest advancements in drug research not only aids comprehension of cutting-edge technologies used in drug development but also fosters invaluable experience and knowledge accumulation while nurturing innovative ideas for future drug discovery.This review comprehensively analyzes the research progress related to approved small molecule drugs,including aspects such as drug design,structural modification,activity enhancement,and druggability improvement.The aim is to provide valuable insights and assistance for researchers in pharmacology.展开更多
Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters poten...Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.展开更多
文摘Computer-aided drug design (CADD) is an interdisciplinary subject, playing a pivotal role during new drug research and development, especially the discovery and optimization of lead compounds. Traditional Chinese Medicine (TCM) modernization is the only way of TCM development and also an effective approach to the development of new drugs and the discovery of potential drug targets (PDTs). Discovery and validation of PTDs has become the “bottle-neck” restricted new drug research and development and is urgently solved. Innovative drug research is of great significance and bright prospects. This paper mainly discusses the “druggability” and specificity of PTDs, the “druglikeness” of drug candidates, the methods and technologies of the discovery and validation of PTDs and their application. It is very important to achieve the invention and innovation strategy “from gene to drug”. In virtue of modern high-new technology, especially CADD, combined with TCM theory, research and develop TCM and initiate an innovating way fitting our country progress. This paper mainly discusses CADD and their application to drug research, especially TCM modernization.
基金supported by the Sichuan Science and Technology Program,China(Grant Nos.:2023ZYD0105 and 2023YFS0343)。
文摘Dental caries,a chronic disease characterized by tooth decay,occupies the second position in terms of disease burden and is primarily caused by cariogenic bacteria,especially Streptococcus mutans,because of its acidogenic,aciduric,and biofilm-forming capabilities.Developing novel targeted anti-virulence agents is always a focal point in caries control to overcome the limitations of conventional anti-virulence agents.The current study represents an up-to-date review of in silico approaches of drug design against dental caries,which have emerged more and more powerful complementary to biochemical attempts.Firstly,we categorize the in silico approaches into computer-aided drug design(CADD)and AI-assisted drug design(AIDD)and highlight the specific methods and models they contain respectively.Subsequently,we detail the design of anti-virulence drugs targeting single or multiple cariogenic virulence targets of S.mutans,such as glucosyltransferases(Gtfs),antigen I/II(AgI/II),sortase A(SrtA),the VicRK signal transduction system and superoxide dismutases(SODs).Finally,we outline the current opportunities and challenges encountered in this field to aid future endeavors and applications of CADD and AIDD in anti-virulence drug design.
基金the financial support from the National Natural Science Foundation of China(Nos.82473781,82173652 and 81872728)the Natural Science Foundation of Jiangsu Province(No.BK20221522)Support from Jiangsu“333 High Level Talents Cultivation”Leading Talents(No.2022–3–16–203)。
文摘The evolution of cancer therapies has highlighted the limitations of traditional chemotherapy,particularly its lack of specificity and off-target toxicities,driving the development of targeted treatments like small molecule-drug conjugates(SMDCs).SMDCs offer distinct advantages over antibody-drug conjugates(ADCs),including simpler synthesis,lower production costs,and improved solid tumor penetration due to their smaller size.However,challenges remain,such as a limited variety of targeting ligands and the complexity of optimizing selectivity and efficacy within the tumor microenvironment.This review focuses on key aspects such as mechanisms of action,biomarker selection,and the optimization of each component of SMDCs.It also covers SMDCs that have been approved or are currently under active clinical trials,while providing insights into future developments in this promising field of targeted cancer therapies.
文摘In the year 1971,the world’s biggest structural biology collaboration name—The Research Collaboratory for Structural Bioinformatics(RCSB),was formed to gather all the structural biologists at a single platform and then extended out to be the world’s most extensive structural data repository named RCSB-Protein Data Bank(PDB)(https://www.rcsb.org/)that has provided the service for more than 50 years and continues its legacy for the discoveries and repositories for structural data.The RCSB has evolved from being a collaboratory network to a full-fledged database and tool with a huge list of protein structures,nucleic acid-containing structures,ModelArchive,and AlphaFold structures,and the best is that it is expanding day by day with computational advancement with tools and visual experiences.In this review article,we have discussed how RCSB has been a successful collaboratory network,its expansion in each decade,and how it has helped the ground-breaking research.The PDB tools that are helping the researchers,yearly data deposition,validation,processing,and suggestions that can help the developer improve for upcoming years are also discussed.This review will help future researchers understand the complete history of RCSB and its developments in each decade and how various future collaborative networks can be developed in various scientific areas and can be successful by keeping RCSB as a case study.
基金The National Natural Science Foundation of China(No.71271053)the Scientific Innovation Research of College Graduates in Jiangsu Province(No.CXLX13_082)
文摘Due to the practical problems of the high costs and the long development cycle of China’s cabinet production,a computer-aided design method of the cabinet based on style imagery is proposed.According to the principle of the conjoint analysis method, the rough set theory and the weight coefficient of different components of the cabinet,a multi-dimensional model of style imagery to evaluate the cabinet is built. Then the related constants of style imagery are calculated and the cabinet components library is also built by the three-dimensional modeling.Finally,with recombinant technology and the mapping model between cabinet style and external characteristics,the prototype system based on Visual Studio is proposed.This system actualizes the bidirectional reasoning between product style imagery and the shape features,which can assist designers to produce more creative designs,greatly improve the efficiency of cabinet development and increase the profits of companies.
基金supported by the National Natural Science Foundation of China[82172086]National Key R&D Program of China[2020YFE0201700]+2 种基金Shenyang Science and Technology Talent Support Program[RC210447]Career Development Program for Young and Middle-aged Teachers of Shenyang Pharmaceutical University[ZQN2019004]“Dual Service”Program of University in Shenyang。
文摘Attributing to their broad pharmacological effects encompassing anti-inflammation,antitoxin,and immunosuppression,glucocorticoids(GCs)are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus,nephritis,arthritis,ulcerative colitis,asthma,keratitis,macular edema,and leukemia.However,longterm use often causes undesirable side effects,including metabolic disorders-induced Cushing's syndrome(buffalo back,full moon face,hyperglycemia,etc.),osteoporosis,aggravated infection,psychosis,glaucoma,and cataract.These notorious side effects seriously compromise patients'quality of life,especially in patients with chronic diseases.Therefore,glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention.Among them,prodrugs have the advantages of low investment,low risk,and high success rate,making them a promising strategy.In this review,we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades,including polymer-based prodrugs,dendrimer-based prodrugs,antibody-drug conjugates,peptide-drug conjugates,carbohydrate-based prodrugs,aliphatic acid-based prodrugs and so on.Besides,we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs.This review is expected to be helpful for the research and development of novel GCs and prodrugs.
文摘The finite element analysis and the optimum design of aluminum profile extrusion mould were investigated using the ANSYS software and its parameterized modeling method. The optimum dimensions of the mould were obtained. It is found that the stress distribution is very uneven, and the stress convergence is rather severe in the bridge of the aluminum profile extrusion mould. The optimum height of the mould is 70.527 mm, and the optimum radius of dividing holes are 70.182 mm and 80.663 mm. Increasing the height of the mould in the range of 61.282 mm to 70.422 mm can prolong its longevity, but when the height is over 70.422 mm, its longevity reduces.
基金financially supported by the FDCT Project 0029/2018/A1the University of Macao Research Grants(MYRG2019-00041-ICMS)performed in part at the High-Performance Computing Cluster(HPCC)which is supported by Information and Communication Technology Office(ICTO)of the University of Macao。
文摘Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.
文摘Thermodynamic and kinetic study on TRIP （transformation induced plasticity） steels, cemented carbides and mold steel for plastics were carried out in order to design modern advanced materials. With the sublattice model, equilibrium compositions of ferrite and austenite phases in TRIP steels, as well as volume fraction of austenite at inter-critical temperatures for different time were calculated. Concentration profiles of carbon, manganese, aluminum and silicon in the steels were also estimated in the lattice fixed frame of reference. The effect of Si and Mn on TRIP was discussed according to thermodynamic and kinetic analyses. In order to understand and produce the graded nanophase structure of cemented carbides, miscellaneous phases in the M-Co-C （M= Ti, Ta, Nh） systems and Co-V-C system were modeled. Solution parameters and thermodynamic： properties were listed in detail. The improvement of machining behavior of prehardened mould steel for plastics was obtained by computer-aided composition design. The results showed that the matrix composition of large-section prehardened mould steel for plastic markedly influences the precipitation of non-metallic inclusion and the composition control by the aid of Thermo-Calc software package minimizes the amount of detrimental oxide inclusion. In addition, the modification of calcium was optimized in composition design.
基金The study was financially supported by the key project of Science and Technology Commission of Shanghai Local Gov-ernment (No. 015211010), the National Natural Science Foundation of China (No. 50171038) and the China-Belgium bi-lateral project (No. 2001-242).
文摘Suitable optimization and simulation were performed using a powerful software package with a mature database as well as modem measurement facilities, which led to the successful designing and manufacturing of advanced steels. In the course of designing, the composition of a large section of prehardened mold steel for plastics was estimated so as to lower the quantities of oxide inclusions to change the type of carbides and to raise the machinability. The composition and process were adjusted to obtain satisfactory surface quality for the prevailing galvanization in transformation-induced plasticity （TRIP） steel. The refuting process of low-carbon steel was simulated in the light of both Thermo-Calc and Factsage. Thermodynamic and kinetic analyses were always conducted during the test and the procedure.
文摘The general computer-aided design （CAD） software cannot meet the mould design requirement of the autoclave process for composites, because many parameters such as temperature and pressure should be considered in the mould design process, in addition to the material and geometry of the part. A framed-mould computer-aided design system （FMCAD） used in the autoclave moulding process is proposed in this paper. A function model of the software is presented, in which influence factors such as part structure, mould structure, and process parameters are considered; a design model of the software is established using object oriented （O-O） technology to integrate the stiffness calculation, temperature field calculation, and deformation field calculation of mould in the design, and in the design model, a hybrid model of mould based on calculation feature and form feature is presented to support those calculations. A prototype system is developed, in which a mould design process wizard is built to integrate the input information, calculation, analysis, data storage, display, and design results of mould design. Finally, three design examples are used to verify the prototype.
基金This work was supported by grants from the National Sciences Fund(31370938 and 81272528)The Fund(81272528)offered experiment material and collected the data for analysisThe Fund(31370938)helped design the study and was helpful in preparing the manuscript.
文摘Fully human antibodies have minimal immunogenicity and safety profiles.At present,most potential antibody drugs in clinical trials are humanized or fully human.Human antibodies are mostly generated using the phage display method(in vitro)or by transgenic mice(in vivo);other methods include B lymphocyte immortalization,human–human hybridoma,and single-cell polymerase chain reaction.Here,we describe a structure-based computer-aided de novo design technology for human antibody generation.Based on the complex structure of human epidermal growth factor receptor 2(HER2)/Herceptin,we first designed six short peptides targeting the potential epitope of HER2 recognized by Herceptin.Next,these peptides were set as complementarity determining regions in a suitable immunoglobulin frame,giving birth to a novel anti-HER2 antibody named "HF,"which possessed higher affinity and more effective anti-tumor activity than Herceptin.Our work offers a useful tool for the quick design and selection of novel human antibodies for basic mechanical research as well as for imaging and clinical applications in immune-related diseases,such as cancer and infectious diseases.
文摘Because of the powerful mapping ability, back propagation neural network (BP-NN) has been employed in computer-aided product design (CAPD) to establish the property prediction model. The backward problem in CAPD is to search for the appropriate structure or composition of the product with desired property, which is an optimization problem. In this paper, a global optimization method of using the a BB algorithm to solve the backward problem is presented. In particular, a convex lower bounding function is constructed for the objective function formulated with BP-NN model, and the calculation of the key parameter a is implemented by recurring to the interval Hessian matrix of the objective function. Two case studies involving the design of dopamine β-hydroxylase (DβH) inhibitors and linear low density polyethylene (LLDPE) nano composites are investigated using the proposed method.
基金supported in part by National Institute of Health(NIH),USA(Grant Nos.:R01GM126189,R01AI164266,and R35GM148196)the National Science Foundation,USA(Grant Nos.DMS2052983,DMS-1761320,and IIS-1900473)+3 种基金National Aero-nautics and Space Administration(NASA),USA(Grant No.:80NSSC21M0023)Michigan State University(MSU)Foundation,USA,Bristol-Myers Squibb(Grant No.:65109)USA,and Pfizer,USAsupported by the National Natural Science Foundation of China(Grant Nos.:11971367,12271416,and 11972266).
文摘Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data,these models showcase remarkable efficacy across various tasks,including new drug design and drug target identification.The adaptability of pre-trained trans-former-based models renders them indispensable assets for driving data-centric advancements in drug discovery,chemistry,and biology,furnishing a robust framework that expedites innovation and dis-covery within these domains.Beyond their technical prowess,the success of transformer-based models in drug discovery,chemistry,and biology extends to their interdisciplinary potential,seamlessly combining biological,physical,chemical,and pharmacological insights to bridge gaps across diverse disciplines.This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields.In our review,we elucidate the myriad applications of transformers in drug discovery,as well as chemistry and biology,spanning from protein design and protein engineering,to molecular dynamics(MD),drug target iden-tification,transformer-enabled drug virtual screening(VS),drug lead optimization,drug addiction,small data set challenges,chemical and biological image analysis,chemical language understanding,and single cell data.Finally,we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.
文摘Custom-made esthetic finger prostheses, which are used for rehabilitation of patients with missing or impaired fingers, have been fabricated manually. However, such fabrication is time-consuming and requires manual skill. Here we propose a computer-aided method for fabricating finger pros-theses to save time and allow fabrications that do not require considerable manual skill. In this method, the dimensions of a patient’s healthy finger on the contralateral hand are first measured using a caliper. Using these dimensions, a three-dimensional model is constructed for fabricating a prosthesis for the patient’s impaired finger. Using the 3D model, a mold is designed using 3D modeling tools and a computer-aided design system. The resulting mold is then fabricated using a 3D printer. A finger prosthesis is fabricated by pouring silicone resin into the mold. A finger prosthesis for a volunteer was experimentally fabricated according to the proposed method. To evaluate the size and shape of the finger prosthesis, the difference between the finger prosthesis and the original finger of the volunteer was analyzed. Because the average difference between them was 0.25 mm, it was concluded that the proposed method could be used to fabricate a finger prosthesis of adequate size and shape.
文摘The article is to study the development of computer-aided design of X-ray microtomography—the device for investigating the structure and construction of three-dimensional images of organic and inorganic objects on the basis of shadow projections. This article provides basic information regarding CAD of X-ray microtomography and a scheme consisting of three levels. The article also shows basic relations of X-ray computed tomography, the generalized scheme of an X-ray microtomographic scanner. The methods of X-ray imaging of the spatial microstructure and morphometry of materials are described. The main characteristics of an X-ray microtomographic scanner, the X-ray source, X-ray optical elements and mechanical components of the positioning system are shown. The block scheme and software functional scheme for intelligent neural network system of analysis of the internal microstructure of objects are presented. The method of choice of design parameters of CAD of X-ray microtomography aims at improving the quality of design and reducing costs of it. It is supposed to reduce the design time and eliminate the growing number of engineers involved in development and construction of X-ray microtomographic scanners.
基金supported by grants from the National Natural Science Foundation of China(No.82273770)the Foundation for Innovative Research Groups of the National Natural Science Foundation of Sichuan Province(No.24NSFTD0051).
文摘In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.
文摘Introduction Since the 21st century,the biomedical field has gained increasing attention.The biomedical field mainly encompasses biology,materials science,pharmacology,and drug delivery,etc.These areas hold significant importance for human society in terms of health protection,disease diagnosis and treatment,via medical technology innovation and drug development.Consequently,scientists place great emphasis on research in this domain.It must be noted that the research process in biomedicine mainly includes topic selection,experimentation,analysis,and summary.Among these,topic selection is a critical step that affects the entire process.This topic selection not only clarifies the direction and objectives of the study but also provides a clear framework for subsequent research,thereby ensuring scientific rigor and effectiveness while laying a solid foundation for the result analysis.Thus,how to approach topic selection is a crucial issue that requires careful consideration.
基金the National Natural Science Foundation of China(No.82304286 by S.Yuan,Nos.U21A20416 and 82020108030 by H.-M.Liu)the Scientific and Technological Project of Henan Province(No.232102311165 by S.Yuan,No.242102311236 by Y.-R.Bai)for financial support。
文摘In 2024,the U.S.Food and Drug Administration approved a total of 50 drug marketing applications,with small molecule drugs accounting for half of the medications.Upon surveying these endorsed pharmaceuticals,it becomes evident that certain structures exhibit familiarity,potentially resulting from structural modifications applied to previously approved drugs.Consequently,exploring the latest advancements in drug research not only aids comprehension of cutting-edge technologies used in drug development but also fosters invaluable experience and knowledge accumulation while nurturing innovative ideas for future drug discovery.This review comprehensively analyzes the research progress related to approved small molecule drugs,including aspects such as drug design,structural modification,activity enhancement,and druggability improvement.The aim is to provide valuable insights and assistance for researchers in pharmacology.
基金National Science and Technology Major Project(Grant No. 2012ZX09506001-004)
文摘Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.
