Docking-MM-GB/SA and ADME Screening of HIV-1 NNRTI Inhibitor: Nevirapine and its Analogues

Nevirapine and its synthetic analogues, a class of non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), have been the objective of numerous studies focused to prepare better and safer anti-HIV drugs. We developed a library of nevirapine analogues (47) using combinatorial design and with structural modification at X, Y and R substituents in the parent structure of nevirapine. Their molecular interactions and binding affinities with reverse transcriptase (3HVT and 1VRT) have been studied using the docking-molecular mechanics based generalized Born/surface area (MM-GB/SA) solvation model. Final screening of these analogues is based on absorption, distribution, metabolism and excretion (ADME) properties. The proposed NNRTI analogues dock in a similar position and orientation in the active site of RT as co-crystallized nevirapine. In addition a linear correlation was observed between the calculated free energy of binding (FEB) and pIC $_{50}$ for the inhibitors with correlation coefficient R $^{2}$ of 0.9948, suggesting that the docked structure orientation and the interaction energies are reasonable. The electrostatic energy terms estimated by GB/SA showed important role on prediction of binding affinity (R $^{2}$ = 17.2%. Since we used two different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different resolution (2.9 and 2.2 Å, we propose that structures with resolutions better than 3 Å can be used to produce reasonable docking results. Few analogues showed high binding affinity and activity with RT in compare to co-crystallized nevirapine. These analogues also well qualify ADME properties and showed good druggable characters. The work addressed to modify the X, Y and R substituents in the nevirapine scaffold to prepare synthetic analogues for second generation drug development against RT.