Affiliations: Department of Bioinformatics and Biotechnology, Jaypee
University of Information Technology, Waknaghat, Distt.-Solan, Himachal
Pradesh, India
Abstract: 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.
Keywords: HIV-I RT, nevirapine and its analogues, docking, glide, MM-GB/SA, free energy of binding, ADME