Docking mode of delvardine and its analogues into the p66 domain of HIV-1 reverse transcriptase: screening using molecular mechanics-generalized born/surface area and absorption, distribution, metabolism and excretion properties

Delvardine and its structural derivatives are important non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). In this work, 15 delvardine analogues were studied. A free energy-of-binding (FEB) expression was developed in the form of an optimized linear combination of van der Waal (vdW), electrostatic, solvation and solvent-accessible surface area (SASA) energy terms. The solvation energy terms estimated by generalized born/surface area (GB/SA) play an important role in predicting the binding affinity of delvardine analogues. Out of 15 derivatives, substitution of CH3 with H at the Y and R positions, as well as substitution of SO2CH3 with only CH2 at the Z position in S2, S8 and S12 analogues, were found to be the most potent (glide score = -7.60, -8.06 and -7.44; pIC50 = 7.28, 7.37 and 7.64) in comparison with the template delvardine (which is used currently as the drug candidate). All the three analogues also passed the absorption, distribution, metabolism and excretion (ADME) screening and Lipinski's rule of 5, and have the potential to be used for second-generation drug development. The work demonstrates that dock molecular mechanics-generalized born/surface area (MM-GB/SA-ADME) is a promising approach to predict the binding activity of ligands to the receptor and further screen for a successful candidate drug in a computer-aided rational drug design.