Improved CoMFA Modeling by Optimization of Settings : Toward the Design of Inhibitors of the HCV NS3 Protease

摘要: In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, series tripeptide inhibitors incorporating mix alpha- and beta-amino acids has been synthesized. To understand the structural implications acid substitution, P(1), P(2), P(3) positions potent scaffold were scanned combined with carboxylic acyl sulfonamide C-terminal groups. Inhibition was evaluated revealed that changes resulted in loss potency compared alpha-peptide analogues. However, several compounds exhibited muM potency. data modeled ligand-protein binding poses how ligand structure affected inhibition The position seemed be least sensitive for substitution. Moreover, importance proper oxyanion hole interaction good suggested by both molecular modeling. gain further insight into requirements inhibitors, three-dimensional quantitative structure-activity relationship (3D-QSAR) model constructed using comparative field analysis (CoMFA). most predictive CoMFA q(2)=0.48 r(pred)(2)=0.68.