Computer Aided Structural Design Study Of Novel Compound Against Hepatitis C Virus

Objective:Hepatitis C is a harmful viral infectious disease infected by hepatitis C virus?HCV?.The treatment of hepatitis C is difficult and anti-HCV vaccine unavailable at present.So hepatitis C is one of the major problems in the world.In this paper,a series of compounds having anti-HCV activity were studied.This study aims to build efficient computational model and provide guidance for designing and selecting new compound structures with anti-HCV activity.Methods:In this paper,two series of compound structures having anti-HCV activity were studied using computer aided drug design method.First of all,computational models were built using the three-dimensional quantitative structure activity relationship?3D-QSAR?and used to analyze the important structural characteristics that affect the activity of the compounds.Then molecular docking was used to analyze the dominant conformation of the compounds at the active site and discussed initially the mechanism of interaction.On this basis,a series of new compound structures having anti-HCV activity were designed and selected.Then OSIRIS Property Explorer was used to evaluate the toxicity and pharmacology of selected compounds with high activity.Results:1.42 4-hydroxyamino ?-pyranone carboxamide analogues were studied using 3D-QSAR and a QSAR model with high reliability and prediction ability was established(20.756,SEE=0.135,R_ext²=0.653,r_boot²=0.955,SEE_boot=0.091,R_p²=0.609,R_m?overall?²=0.680),then the structural features of affecting the activity of inhibitor were analyzed and 103 new compounds structure having anti-HCV activity were designed and screened on the basis of the contour maps,and the activity of these compounds were predicted.Then OSIRIS Property Explorer were used to evaluate the toxicity and pharmacology of 40 compounds with high activity.Through the comprehensive analysis,compound 2578 was selected the optimal structure.2.48 HCV NS5 B polymerase inhibitors were studied using 3D-QSAR and molecular docking.The QSAR model were built on the basis of structures and activity of compounds,and the optimal model was validated(q² = 0.627,r² = 0.943,F value is 86.182,SEE=0.221,R_ext²=0.629,r_boot²=0.975,SEE_boot=0.141,R_p²=0.697,R_m?overall?²=0.835),those results indicated that the model has the reliability and high prediction ability.136 new compounds with anti-HCV activity were designed and selected based on the analysis of the contour and results of molecular docking,and their activities were predicted.Then OSIRIS Property Explorer was used to evaluate the toxicity and pharmacology of 43 compounds with high activity.Through the comprehensive analysis,compound 130 was selected the optimal structure.Conclusion:In this paper,combination of these computer aided drug design methods such as 3D-QSAR and molecular docking were used to systematic study two series of compounds with anti-HCV activity.This study provided guidance for designing new compound structures with anti-HCV activity by analyzing structure features affecting inhibitor activity.Moreover,this study provides theoretical basis and new ideas for research and development and screen of hepatitis C drugs.