Dipole Moment, Solvation Energy, and Ovality Account for the Variations in the Biological Activity of HIV-1 Reverse Transcriptase Inhibitor Fragments

Objective: A computational approach was employed to determine the interaction of molecular descriptors and the biological activity of the different fragments of HIV-1 reverse transcriptase inhibitors (RTIs).

Methods: Using multiple linear regression analysis and leave-one-out validation method, a quantitative structure activity relationship (QSAR) model was developed to relate the biological activity (log IC50) of the different fragment-sized compounds against HIV-1 RT(WT) DNA-dependent DNA polymerase and molecular descriptors of these compounds.

Results: QSAR model identified dipole moment, solvation energy, and ovality of fragment-sized compounds to confer reverse transcriptase inhibitory action. A highly significant correlation with log P, molecular weight, polarizability, molecular energy, zero-point energy, constant volume heat capacity at 298 K, and entropy was identified to account for the variations in the potency of RTIs. An increase in ovality, log P, and molecular weight of the fragment-sized compound renders a more active reverse transcriptase inhibition.

Conclusion: The quality of the established QSAR model has been validated and demonstrates its potential as a tool for computational design and synthesis of next generation RTIs.