| Abstract
| - A set of 113 flexible cyclic urea inhibitors of human immunodeficiency virus protease (HIV-1 PR) wasused to compare the quality and predictive power of CoMFA and CoMSIA models for manually orautomatically aligned inhibitor set. Inhibitors that were aligned automatically with molecular docking werein agreement with information obtained from existing X-ray structures. Both alignment methods producedstatistically significant CoMFA and CoMSIA models, with the best q2 value being 0.649 and the best predictiver2 being 0.754. The manual alignment gave statistically higher values, whereas the automated alignmentgave more robust models for predicting the activities of an external inhibitor set. Both models utilizedsimilar amino acids in the HIV-1 PR active site, supporting the idea that hydrogen bonds form between aninhibitor and the backbone carbonyl oxygens of Gly48 and Gly48‘ and also the backbone NH group ofAsp30, Gly48, Asp29‘, and Gly48‘ of the enzyme. These results suggest that an automated inhibitor alignmentcan yield predictive 3D QSAR models that are well comparable to manual methods. Thus, an automatedalignment method in creating 3D QSAR models is encouragable when a well-characterized structure of thetarget protein is available.
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