The papain-like protease(PLpro)is vital for the replication of coronaviruses(Co Vs),as well as for escaping innate-immune responses of the host.Hence,it has emerged as an attractive antiviral drug-target.In this study...The papain-like protease(PLpro)is vital for the replication of coronaviruses(Co Vs),as well as for escaping innate-immune responses of the host.Hence,it has emerged as an attractive antiviral drug-target.In this study,computational approaches were employed,mainly the structure-based virtual screening coupled with all-atom molecular dynamics(MD)simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)PLpro,which can be further developed as potential pan-PLprobased broad-spectrum antiviral drugs.The sequence,structure,and functional conserveness of most deadly human Co Vs PLprowere explored,and it was revealed that functionally important catalytic triad residues are well conserved among SARS-Co V,SARS-Co V-2,and middle east respiratory syndrome coronavirus(MERS-Co V).The subsequent screening of a focused protease inhibitors database composed of^7,000 compounds resulted in the identification of three candidate compounds,ADM13083841,LMG15521745,and SYN15517940.These three compounds established conserved interactions which were further explored through MD simulations,free energy calculations,and residual energy contribution estimated by MM-PB(GB)SA method.All these compounds showed stable conformation and interacted well with the active residues of SARS-Co V-2 PLpro,and showed consistent interaction profile with SARS-Co V PLproand MERS-Co V PLproas well.Conclusively,the reported SARS-Co V-2 PLprospecific compounds could serve as seeds for developing potent pan-PLprobased broad-spectrum antiviral drugs against deadly human coronaviruses.Moreover,the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.展开更多
Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint k...Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.展开更多
基金the Starting Research Grant for High-level Talents from Guangxi Universitythe Postdoctoral Project from Guangxi University。
文摘The papain-like protease(PLpro)is vital for the replication of coronaviruses(Co Vs),as well as for escaping innate-immune responses of the host.Hence,it has emerged as an attractive antiviral drug-target.In this study,computational approaches were employed,mainly the structure-based virtual screening coupled with all-atom molecular dynamics(MD)simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)PLpro,which can be further developed as potential pan-PLprobased broad-spectrum antiviral drugs.The sequence,structure,and functional conserveness of most deadly human Co Vs PLprowere explored,and it was revealed that functionally important catalytic triad residues are well conserved among SARS-Co V,SARS-Co V-2,and middle east respiratory syndrome coronavirus(MERS-Co V).The subsequent screening of a focused protease inhibitors database composed of^7,000 compounds resulted in the identification of three candidate compounds,ADM13083841,LMG15521745,and SYN15517940.These three compounds established conserved interactions which were further explored through MD simulations,free energy calculations,and residual energy contribution estimated by MM-PB(GB)SA method.All these compounds showed stable conformation and interacted well with the active residues of SARS-Co V-2 PLpro,and showed consistent interaction profile with SARS-Co V PLproand MERS-Co V PLproas well.Conclusively,the reported SARS-Co V-2 PLprospecific compounds could serve as seeds for developing potent pan-PLprobased broad-spectrum antiviral drugs against deadly human coronaviruses.Moreover,the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.
文摘Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.
