A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: Contribution of conformational flexibility to inhibitory activity.

Keigo Gohda

doi:10.1080/14756360600810233

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A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: Contribution of conformational flexibility to inhibitory activity.

Keigo Gohda

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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.

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Aspartic Acid Computer Simulation HIV Protease HIV Protease Inhibitors Models, Biological Molecular Structure Pliability Protein Binding Protons Quantitative Structure-Activity Relationship Journal Article

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Keigo Gohda. 2006. A quantitative structure-activity relationship study for structurally diverse HIV-1 protease inhibitors: Contribution of conformational flexibility to inhibitory activity.. https://doi.org/10.1080/14756360600810233

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