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
Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing p...Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.展开更多
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
The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be in...The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.展开更多
Many recent advances in biomedical research are related to the combination of biology and microengineering. Microfluidic devices, such as organ-on-a-chip systems, integrate with living cells to allow for the detailed ...Many recent advances in biomedical research are related to the combination of biology and microengineering. Microfluidic devices, such as organ-on-a-chip systems, integrate with living cells to allow for the detailed in vitro study of human physiology and pathophysiology. With the poor translation from animal models to human models, the organ-on-a-chip technology has become a promising substitute for animal testing, and their small scale enables precise control of culture conditions and high-throughput experiments, which would not be an economically sound model on a macroscopic level. These devices are becoming more and more common in research centers, clinics, and hospitals, and are contributing to more accurate studies and therapies, making them a staple technology for future drug design.展开更多
In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of...In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.展开更多
Over the last decade,deep learning(DL)methods have been extremely successful and widely used in almost every domain.Researchers are now focusing on the convergence of medical imaging and drug design using deep learnin...Over the last decade,deep learning(DL)methods have been extremely successful and widely used in almost every domain.Researchers are now focusing on the convergence of medical imaging and drug design using deep learning to revolutionize medical diagnostic and improvement in the monitoring from response to therapy.DL a new machine learning paradigm that focuses on learning with deep hierarchical models of data.Medical imaging has transformed healthcare science,it was thought of as a diagnostic tool for disease,but now it is also used in drug design.Advances in medical imaging technology have enabled scientists to detect events at the cellular level.The role of medical imaging in drug design includes identification of likely responders,detection,diagnosis,evaluation,therapy monitoring,and follow-up.A qualitative medical image is transformed into a quantitative biomarker or surrogate endpoint useful in drug design decision-making.For this,a parameter needs to be identified that characterizes the disease baseline and its subsequent response to treatment.The result is a quantifiable improvement in healthcare quality in most therapeutic areas,resulting in improvements in quality and life duration.This paper provides an overview of recent studies on applying the deep learning method in medical imaging and drug design.We briefly discuss the fields related to the history of deep learning,medical imaging,and drug design.展开更多
Objectives： Computational study will help us in reducing the experimental work. The process of drug discovery involves the designing of molecules with appropriate pharmacophores with the help of various soft wares. T...Objectives： Computational study will help us in reducing the experimental work. The process of drug discovery involves the designing of molecules with appropriate pharmacophores with the help of various soft wares. The purpose of this paper is to study the probable binding modes of fatty acids on fatty acids after enzymatic hydrolysis of the FAAH （fatty acid amide hydrolase） in different extracts of flowers, leaves, stem bark, root bark and nuts of Semecarpus anacardiurn L. f. by using molecular modeling study and computer assisted drug designing. Nuts yielded 20 fatty acids including saturated, ω-3 unsaturated, ω-6 unsaturated, ω-7 unsaturated and ω-9 unsaturated fatty acids. Based on IR, IH NMR, 13C NMR, MS （mass） spectrometry, GC analysis, the structural elucidation of these isolated fatty acids was established. Methods： A dataset comprising of 20 fatty acids were drawn in ChemDraw and converted into 3D-molecules with all possible tautomers and chiral centers. The minimization of molecules was carried out using PRCG （Polak-Ribiere Conjugate Gradient） method with maximum of 5000 iterations. The minimized compounds were used for protein preparation. The crystal structure of human FAAH （PDB ID： 3K84） is prepared and selected for the docking studies of 20 fatty acids using Schr6dinger docking program module.. Conclusions： In this study, we carried out the molecular docking studies in order to understand the probable binding mode of 20 fatty acids in FAAH from which we identified key active site residues for FAAH, thereby it can be used to design the novel compounds for FAAH targets.展开更多
Inflammatory bowel diseases(IBD)significantly contribute to high mortality globally and negatively affect patients’qualifications of life.The gastrointestinal tract has unique anatomical characteristics and physiolog...Inflammatory bowel diseases(IBD)significantly contribute to high mortality globally and negatively affect patients’qualifications of life.The gastrointestinal tract has unique anatomical characteristics and physiological environment limitations.Moreover,certain natural or synthetic anti-inflammatory drugs are associated with poor targeting,low drug accumulation at the lesion site,and other side effects,hindering them from exerting their therapeutic effects.Colon-targeted drug delivery systems represent attractive alternatives as novel carriers for IBD treatment.This review mainly discusses the treatment status of IBD,obstacles to drug delivery,design strategies of colon-targeted delivery systems,and perspectives on the existing complementary therapies.Moreover,based on recent reports,we summarized the therapeutic mechanism of colon-targeted drug delivery.Finally,we addressed the challenges and future directions to facilitate the exploitation of advanced nanomedicine for IBD therapy.展开更多
γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the ...γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.展开更多
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.
基金We thank the Ministry of Science and Technology of China(2019YFA0508400 and 2016YFA0500700)the National Natural Science Foundation of China(21874123 and 21807095)Collaborative Innovation Program of Hefei Science Center,CAS(2020HSC-CIP009)for the financial support.
文摘Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.
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Financial support from the University of Copenhagen and the Phospholipid Research Center(Heidelberg,Germany)is kindly acknowledged
文摘The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.
文摘Many recent advances in biomedical research are related to the combination of biology and microengineering. Microfluidic devices, such as organ-on-a-chip systems, integrate with living cells to allow for the detailed in vitro study of human physiology and pathophysiology. With the poor translation from animal models to human models, the organ-on-a-chip technology has become a promising substitute for animal testing, and their small scale enables precise control of culture conditions and high-throughput experiments, which would not be an economically sound model on a macroscopic level. These devices are becoming more and more common in research centers, clinics, and hospitals, and are contributing to more accurate studies and therapies, making them a staple technology for future drug design.
基金supported by SIP-IPN,CONACYT (CB-168116)FIS/IMSS (FIS/IMSS/PROT/G11-2/1013)
文摘In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.
文摘Over the last decade,deep learning(DL)methods have been extremely successful and widely used in almost every domain.Researchers are now focusing on the convergence of medical imaging and drug design using deep learning to revolutionize medical diagnostic and improvement in the monitoring from response to therapy.DL a new machine learning paradigm that focuses on learning with deep hierarchical models of data.Medical imaging has transformed healthcare science,it was thought of as a diagnostic tool for disease,but now it is also used in drug design.Advances in medical imaging technology have enabled scientists to detect events at the cellular level.The role of medical imaging in drug design includes identification of likely responders,detection,diagnosis,evaluation,therapy monitoring,and follow-up.A qualitative medical image is transformed into a quantitative biomarker or surrogate endpoint useful in drug design decision-making.For this,a parameter needs to be identified that characterizes the disease baseline and its subsequent response to treatment.The result is a quantifiable improvement in healthcare quality in most therapeutic areas,resulting in improvements in quality and life duration.This paper provides an overview of recent studies on applying the deep learning method in medical imaging and drug design.We briefly discuss the fields related to the history of deep learning,medical imaging,and drug design.
文摘Objectives： Computational study will help us in reducing the experimental work. The process of drug discovery involves the designing of molecules with appropriate pharmacophores with the help of various soft wares. The purpose of this paper is to study the probable binding modes of fatty acids on fatty acids after enzymatic hydrolysis of the FAAH （fatty acid amide hydrolase） in different extracts of flowers, leaves, stem bark, root bark and nuts of Semecarpus anacardiurn L. f. by using molecular modeling study and computer assisted drug designing. Nuts yielded 20 fatty acids including saturated, ω-3 unsaturated, ω-6 unsaturated, ω-7 unsaturated and ω-9 unsaturated fatty acids. Based on IR, IH NMR, 13C NMR, MS （mass） spectrometry, GC analysis, the structural elucidation of these isolated fatty acids was established. Methods： A dataset comprising of 20 fatty acids were drawn in ChemDraw and converted into 3D-molecules with all possible tautomers and chiral centers. The minimization of molecules was carried out using PRCG （Polak-Ribiere Conjugate Gradient） method with maximum of 5000 iterations. The minimized compounds were used for protein preparation. The crystal structure of human FAAH （PDB ID： 3K84） is prepared and selected for the docking studies of 20 fatty acids using Schr6dinger docking program module.. Conclusions： In this study, we carried out the molecular docking studies in order to understand the probable binding mode of 20 fatty acids in FAAH from which we identified key active site residues for FAAH, thereby it can be used to design the novel compounds for FAAH targets.
基金supported by CACMS Innovation Fund(CI2021B016,CI2021A04801)National Natural Science Foundation of China(82192913,82174073)+2 种基金Qihuang Scholar ProgramCACMS Foundation(ZZ13-035-10)China Postdoctoral Science Foundation(2023M733913).
文摘Inflammatory bowel diseases(IBD)significantly contribute to high mortality globally and negatively affect patients’qualifications of life.The gastrointestinal tract has unique anatomical characteristics and physiological environment limitations.Moreover,certain natural or synthetic anti-inflammatory drugs are associated with poor targeting,low drug accumulation at the lesion site,and other side effects,hindering them from exerting their therapeutic effects.Colon-targeted drug delivery systems represent attractive alternatives as novel carriers for IBD treatment.This review mainly discusses the treatment status of IBD,obstacles to drug delivery,design strategies of colon-targeted delivery systems,and perspectives on the existing complementary therapies.Moreover,based on recent reports,we summarized the therapeutic mechanism of colon-targeted drug delivery.Finally,we addressed the challenges and future directions to facilitate the exploitation of advanced nanomedicine for IBD therapy.
基金supported in part by Award 2121063 from National Science Foundation(to YM)AG66986 from the National Institutes of Health(to MSW).
文摘γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.
