Effect of Polarization of Ligand Charges and Estimation of MM/GBSA Binding Free Energies of Some Pyrazolo[3,4-d]pyrimidine Inhibitors of Mycobacterium Tuberculosis in View of Experimental Results

Background: Pyrazolo[3,4-d]pyrimidine compounds are reported to exhibit various pharmacological activities including antitubercular. The mycobacterium trifunctional enzyme_mtTFE is a vital constituent of β-oxidation pathway for lipid metabolism of tubercle bacillus. Method: In this article, the quantum polarized ligand docking of some pyrazolo[3,4-d]pyrimidine molecules have been conducted within the active site of mtTFE of tubercle bacillus and the effect of the polarization of ligands in the active site resulting from the residues of the binding site have been investigated. The charges of the ligands were calculated using density functional B3LYP/6-31G** level. Binding free energy calculations have been carried out through MM/GBSA method. Results: This study examines comparative performance of fixed point charge based Glide SP docking and the quantum polarized ligand docking strategies. Because of the polarization of charges, significant changes in docking scores have been detected. MM/GBSA free energy calculations of the ligands with mtTFE show good agreement with experimental observations reported in literature. Conclusion: Electrostatic interaction play important role in binding between ligand and receptor. Molecules 2 and 6 have better binding capabilities with mycobacterial β-oxidation trifunctional enzyme_ mtTFE satisfying ADME parameters.