Molecular dynamics and DFT study on the structure and dynamics of N-terminal domain HIV-1 capsid inhibitors

HIV-1 infection is a major threat in the world and has drawn much attention. The emergence of drug-resistance to most of the HIV-1 inhibitors has led to the crucial call for new inhibitors that can interact with the amino terminal domain of HIV-1 CAPSID (CA) and disrupt viral replication. In this study, molecular dynamics simulation was performed on two class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6 one (pyrrolopyrazolone) HIV-1 inhibitors (BI-1 and BI-2) reported to inhibit early postentry stages of viral replication. The effect of N-methylation on the binding of BI-1 and BI-2 to N-terminal HIV-1 capsid of the enzyme was also studied and the structural features such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), the radius of gyration (Rg) were analysed. Density functional theory (DFT) calculations using M06/6311++G(2d,2p) was employed to further investigate the nature of charge transfer of inhibitors based on the second-order perturbation theory. Results obtained showed that N-methylation enhanced the binding of BI-1 with MMPBSA binding energy of −6.2 kcal mol⁻¹ compared to −4.2 kcal mol⁻¹ of BI-1. N-methylation did not have a considerable effect on the binding energy of BI-2, but the MMPBSA binding energy (BI-2_N-methyl) is better, compared to BI-1 and its N-methylated analogue (BI-1_N-methyl). The MMPBSA energies were consistent with the experimental findings.