An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L↑N↑L PR mutant

Abstract

The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L↑N↑L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L↑N↑L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bond interactions is discussed using the atoms in molecules (AIM) analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L↑N↑L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L↑N↑L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs.

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

“…Further analyses included system stability estimation and ligand−enzyme interaction profiling. Previous literature 49,99,100 showed the hybrid B3LYP approach is sufficient with relative energies in good trend with experimental values. Therefore, we selected the B3LYP/6-31+G(d):AMBER ONIOM level to optimize the metal complexes, CYP3A4, and Cu complex−CYP3A4 systems.…”

Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies

“…In all cases, fine details of side-chain interactions were detected on the atomic level, which could improve the efficacy of the corresponding modified compound. In a comprehensive investigation of nine U.S. Food and Drug Administration (FDA) approved drugs, the causes for the reduced binding of most of them to the South African C subtype (C-SA) were revealed in atomic detail [45]. Some HIV protease inhibitors only gained academic interest, e.g., the metallacarborane complexes, exhibiting two cage-like C 2 B 9 H 11 coordinated by a Co 2+ center [46,47].…”

Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

“…Therefore, the development of TYR inhibitors with efficient bioactivity and less toxicity is a relevant branch of scientific research. Recently, we have used molecular modeling approaches to investigate biomolecular systems with an emphasis on enzymatic reactions and inhibition [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”