title: A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: Contribution of conformational flexibility to inhibitory activity.
abstract: In this study, we investigated by linear regression model the SAR data of the 15 HIV-1 protease inhibitors possessing structurally diverse scaffolds. First, a regression model was developed only using the enzyme-inhibitor interaction energy as a term of the model, but did not provide a good correlation with the inhibitory activity (R2 = 0.580 and Q2 = 0.500). Then, we focused on the conformational flexibility of the inhibitors which may represent the diversity of the inhibitors, and added two conformational parameters into the model, respectively: the number of rotatable bonds of ligands (deltaSrot) and the distortion energy of ligands (deltaElig). The regression model by adding deltaElig successfully improved the quality of the model (R2 = 0.771 and Q2 = 0.713) while the model with deltaSrot was unsuccessful. The prediction for a training inhibitor by the deltaElig model also showed good agreement with experimental activity. These results suggest that the conformational flexibility of HIV-1 protease inhibitors directly contributes to the enzyme inhibition.
authors.affiliation: Computer-Aided Molecular Modeling Research Center Kansai (CAMM Kansai), 2-8-20-404, Mikagehonmachi, Higashinada-ku Kobe 658-0046, Japan. ke.gohda@camm-kansai.org
authors.forename: Keigo
authors.initials: K
authors.lastname: Gohda
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008954:Models, Biological; D015394:Molecular Structure; D018583:Pliability; D011485:Protein Binding; D011522:Protons; D021281:Quantitative Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D011522:Protons; D001224:Aspartic Acid; D016333:HIV Protease