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 pIC50 for the inhibitors with correlation coefficient R2 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 (R2 = 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