Novel Quantitative Structure-Activity Studies of HIV-1 Protease Inhibitors of the Cyclic Urea Type Using Descriptors Derived from Molecular Dynamics and Molecular Orbital Calculations

Tatsusada      Yoshida; Toshio      Fujita; Hiroshi      Chuman

Abstract

Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential enzyme for the replication cycle of HIV-1. HIV-1 PR inhibitors have been extensively investigated as anti-AIDS drugs. For developments of HIV-1 PR inhibitors more promising than those utilized at the moment, the construction of reliable QSAR models that can elucidate the inhibitory mechanism as consistently as possible should be one of the most significant issues. Garg, Kurup, and their groups published comprehensive QSAR studies using past structure-activity data for HIV-1 PR inhibitors, and summarized some physicochemical structural factors of inhibitors that govern variations in the inhibitory activity for various structural types. There seem to exist much to be clarified further, especially for effects of electronic structure of inhibitors. It is also expected to incorporate structural and physicochemical information about the enzyme protein into the QSAR model. In this article, we reviewed our own QSAR study on a series of cyclic urea inhibitors with newly proposed QSAR descriptors. We performed molecular dynamics simulations of HIV-1 PR-inhibitor complexes to provide the accurate geometry to the fragment molecular orbital (FMO) calculations as well as to the estimation of an accessible surface area descriptor for inhibitors and amino acid residues. With the FMO procedure to cover full electronic feature of three-dimensional structure of protease-inhibitor complexes, we derived electronic descriptors for inhibitors and amino acid residues. The successful results are believed to provide a new insight into QSAR and understanding of binding mechanism of inhibitors with HIV-1 PR at atomic and electronic levels.

Keywords: Ab initio fragment molecular orbital (FMO), accessible surface area (ASA), charge transfer, cyclic urea type inhibitor (CUI), HIV-1 protease (HIV-1 PR), Inter-fragment interaction energy (IFIE), molecular dynamics (MD), quantitative structure-activity relationship (QSAR)