QSAR Study Of Peptides And Peptoids

Peptides are one of the indispensable substances in life,the use of computer aided drug design（CADD）methods to design peptides and peptiodmimetics can short design cycle,save research funding,improve the level of whole research to a large extent and guide the discovery of new drugs.In this paper,different peptides and peptoids were studied by comparative molecular field analysis（CoMFA）,comparative molecular similarity indices analysis（CoMSIA）,Topomer comparative molecular field analysis（Topomer CoMFA）,quantitative structure-activity relationship（QSAR）,molecular design and molecular docking,which provided theoretical for designing high activities peptides and peptoids.The research of this paper includes as follows:1.CoMFA method was used to build 3D-QSAR model for antimicrobial peptides.The results shown that the established model has a great statistical stability and predictability for antimicrobial peptides(nine AMPs:correlation coefficient（q²）,non-cross-validation correlation coefficient（r²）,external validation statistic(Q²_ext)were 0.537,0.961,0.883,respectively;fourteen AMPs:q²,r²,Q²_ext were 0.502,0.718,0.645,respectively;eighteen AMPs:q²,r²,Q²_extxt were 0.550,0.967,0.989,respectively.).The counter map not only explains the relationship between peptides structure and activity,but also provides the basis for antimicrobial peptides further research.2.58 angiotensin converting enzyme（ACE）inhibitors dipeptide 3D-QSAR model were established based on the method of CoMFA and CoMSIA.The result shown that the CoMFA model with q²,r² and Q²_ext value of 0.940,0.952,0.920;and the CoMSIA model with q²,r² and Q²_ext value of 0.872,0.926 and0.868.The statistic parameters shown that the established model has good fitting ability and predictive ability.Based on the contour maps,eight new ACE inhibitors were designed.Finally the template molecular and new designed compounds and 1O86 were used to explored the binding relationship between the ligands and the receptor protein by using molecular docking.The result shown that there are several hydrogen bonding between the ACE dipeptides with amino acid residues.3.CoMFA and CoMSIA method were used to build melittin and amoebapore 3D-QSAR model.The result shown that,the q² and r² were 0.583and 0.972 for melittin CoMFA model,q² and r² were 0.630 and 0.995 for the best CoMSIA model;the q² and r² were 0.645 and 0.993 for the amoebapore Co MFA model,q² and r² were 0.738 and 0.996 for the best CoMSIA model.The result demonstrated that the established model have high statistical stability,and can provide theoretical for designing polypeptide drugs.4.45 sulfonylurea analogues were established to 3D-QSAR model by using Co MFA,CoMSIA and Topomer CoMFA method.The result shown that the Co MFA model:the q²,r²,Q²_ext were 0.938,0.973,0.847,respectively;the Co MSIA model:the q²,r²,Q²_ext were 0.943,0.955,0.933,respectively;the Topomer Co MFA model:the q²,r²,Q²_ext were 0.884,0.908,0.857,respectively.The biological evaluation demonstrated that the obtained model had good estimation stability.According to the Topomer CoMFA result,new compounds were designed by using Topomer Search technology.The action mechanism of ligands and receptor protein was studied by using molecular docking,and the result shown that the ligands would form the hydrogen-bonding interactions with Arg 380,Asp 379,Thr 198 and Lys 251.5.CoMFA,CoMSIA and Topomer Co MFA method were used to build a3D-QSAR model for 50 indolocarbazole series as cyclin-dependent kinase inhibitors（CDKs）.The result shown that the CoMFA model:the q²,r²,Q²_extxt were 0.907,0.983,0.933,respectively;the Co MSIA model:the q²,r²,Q²_ext were0.944,0.955,0.933,respectively;the Topomer CoMFA model:the q²,r²,Q²_extxt were 0.953,0.968,0.954,respectively.It is demonstrated that this model have good prediction ability.Based on the methodology of fragment-based drug design（FBDD）,new CDKs were designed by using Topomer Search technology.By using molecular docking,the action mechanism of drug and acceptor was studied,and the results showed that inhibitors and amino acid residues had hydrogen binding interaction.