The Quantitative Structure-Activity Relationship Of Enzyme Inhibitors Based On Topomer CoMFA

Computer Aided Drug Design?CADD?is a combination of computer science,chemistry,statistics and other disciplines,and it can theorize the drug design process by using computer simulation.It not only avoids the blindness in the development of new drugs,but also reduces the cycle of drug research and development while saving a lot of resources.In this paper,the Topomer CoMFA,Topomer search and TOPKAT were used as 3D-Quantitative Structure-Activity Relationship?3D-QSAR?study methods for three proteasome inhibitors and one polymerase inhibitor.The main research contents of this paper are as follows:1.The Topomer CoMFA was adopted to study the three-dimensional quantitative structure-activity relationship?3D-QSAR?for 44 boric acid derivatives of Tyropetin inhibitors.The correlation coefficient of cross-validation?r²?,non cross-validation?q²?and external validation(q²_pred)were 0.612,0.985,0.963 respectively.Topomer search was used to search R-groups with special activity contribution from ZINC database.By the highest active molecule filtering 7 R₁ group and 5 R₃ groups were selected.Finally,20 new compounds with higher activities than that of the template molecule were acquired.The result indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability.Topomer Search could be effectively used to screen and had good predictive capability to guide the design of new New Enzyme Inhibitors.2.A 3D-QSAR model involving for 40 dipeptidyl boronic acid proteasome inhibitors was built based on Topomer CoMFA,the multiple correlation coefficient of fitting?r²?,cross-validation?q²?and external validation(q²_pred)were 0.908,0.647 and 0.703,respectively.Topomer Search was employed as a tool for virtual screening in lead-like compounds of ZINC database based on the results of the Topomer CoMFA.Finally,1 R₁ group,7 R₂ groups and 6 R₃ groups with higher contribution values were employed to alternately substitute for the R₁,R₂ and R₃ of template compound 23 with highest bioactivity.As a consequence,33 new molecules with higher activity than that of template molecular were designed successfully.The results showed that the Topomer Search technology could be effectively apply to screen and design new dipeptidyl boronic acid proteasome inhibitors and had good predictive capability to design new dipeptidyl boronic acid proteasome inhibitors drugs as a guidance.3.Three-dimensional quantitative structure-activity relationship?QSAR?models of 39 peptidyl vinyl sulfone cysteine protease inhibitors had been constructed using Topomer CoMFA.The multiple correlation coefficient of fitting?r²?,cross-validation?q²?and external validation(q²_pred)were 0.902,0.685and 0.763,respectively.The results showed that the model not only has good estimation stability but also good prediction capability.Topomer Search was employed to virtually screen lead-like compounds in the ZINC database.Then,four R₁ groups,four R₂ groups and two R₃ groups with higher contribution values were employed to substitute for the R₁,R₂ and R₃ groups in the template compound 28 which had the highest bioactivity.As a result,22 new molecules with higher predicted activity than that of the template molecule were generated.The results showed that the Topomer Search technology could be effectively applied to screen and design new peptidyl vinyl sulfone cysteine protease inhibitors.Finally,the TOPKAT for the five newly designed molecules with the highest predicted activities were examined.The results demonstrated the efficacy of this approach for generating new antimalarial drugs.4.Three-dimensional quantitative structure-activity relationship?QSAR?models of 42 4-hydroxyamino?-pyranone carboxamide analogues had been constructed using Topomer CoMFA.The multiple correlation coefficient of fitting?r²?,cross-validation?q²?and external validation(q²_pred)were 0.909,0.615and 0.967,respectively.The results showed that the model not only had good estimation stability but also good prediction capability.Topomer Search was employed to virtually screen lead-like compounds in the ZINC database.Then,six R₁ groups and four R₂ groups with higher contribution values were employed to substitute for the R₁ and R₂ groups in the template compound 21 which had the highest bioactivity.As a result,22 new molecules with higher predicted activity than that of the template molecule were generated.The results showed that the Topomer Search technology could be effectively applied to screen and design new 4-hydroxyamino?-pyranone carboxamide analogues.Finally,the TOPKAT for the five newly designed molecules with the highest predicted activities were examined.The results demonstrated the efficacy of this approach for generating new anti-HCV drugs.