Design of novel leads: ligand based computational modeling studies on non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1

Abstract

Researchers are on the constant lookout for new antiviral agents for the treatment of AIDS. In the present work, ligand based modeling studies are performed on analogues of substituted phenyl-thio-thymines, which act as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and novel leads are extracted. Using alignment-dependent descriptors, based on group center overlap (SALL, HDALL, HAALL and RALL), an alignment-independent descriptor (S log P), a topological descriptor (Balaban index (J)) and a 3D descriptor dipole moment (μ) and shape based descriptors (Kappa 2 index ((2)κ)), a correlation is derived with inhibitory activity. Linear and non-linear techniques have been used to achieve the goal. Support Vector Machine (SVM, R = 0.929, R(2) = 0.863) and Back Propagation Neural Network (BPNN, R = 0.928, R(2) = 0.861) methods yielded near similar results and outperformed Multiple Linear Regression (MLR, R = 0.915, R(2) = 0.837). The predictive ability of the models are cross-validated using a test dataset (SVM: R = 0.846, R(2) = 0.716, BPNN: R = 0.841, R(2) = 0.707 and MLR: R = 0.833, R(2) = 0.694). It is concluded that the hydrophobicity (S log P) and the polarity (μ) of a ligand and the presence of hydrogen donor (HDALL) moieties are the deciding factors in improving antiviral activity and pharmaco-therapeutic properties. Based on the above findings, a virtual dataset is created to extract probable leads with reasonable antiviral activity as well as better pharmacophoric properties.