Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV‐1 protease by enhanced conformational sampling

Abstract

Recently, allosteric regulations of HIV-1 protease (PR) are suggested as a promising approach to relieve drug resistance of mutations toward inhibitors targeting the active site of PR. Replicaexchange molecular dynamics (REMD) simulations and normal mode analysis (NMA) are integrated to enhance conformational sampling of PR. Molecular mechanics generalized Born surface area (MM-GBSA) method was applied to calculate binding free energies of three inhibitors APV, DRV, and NIT to the wild-type (WT) and multidrug resistance (MDR) PRs. The results suggest that binding free energies of APV and DRV are decreased in the MDR PR relative to the WT PR, suggesting drug resistance of mutations on these two inhibitors. However, the binding ability of the allosteric inhibitor NIT is not impaired in the MDR PR. In addition, internal dynamics analysis based on REMD simulations proves that mutations hardly produce obvious effect on the conformation of the MDR PR in comparison to the WT PR. Scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with residues of PRs on the concatenated trajectories of REMD demonstrates that mutations change the symmetric interaction networks of APV and DRV with PR, but do not generate obvious influence on the asymmetric interaction network of NIT with PR. In summary, allosteric inhibitor NIT can adapt the MDR PR better than those inhibitors toward the active site of PR, thus allosteric inhibitors of PR may be a possible channel to overcome drug resistance of PR.

The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation

“…In order to identify the residues that play an important role in the binding of the DRV to proteases, in WT-Pr-D and MUT-Pr-D the MM-PBSA approach was used ( Supplementary Table S1 ; Figure 6 ). As seen, the residues A28, I50, I84, A28’, I50’, and I84’ of WT-Pr play an important role in binding to the DRV, which is consistent with the previously reported results ( Meher and Wang, 2012 ; Chen et al, 2018 ). On the other hand, the energy analysis also showed the main unfavorable binding energy of D25, D30, D29’, and G48 residues to DRV in WT-Pr.…”

“…Briefly, our results showed that the hydrogen bonding network was disturbed in MUT-Pr, leading to a decreased potency of DRV binding to the active site. This could cause resistance against DRV ( Chen et al, 2018 ; Henes et al, 2019 ), as discussed in Sections 3.3 and 3.4 .…”

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes

“…Up to now, multiple simulation methods, including conventional molecular dynamics (cMD), [54][55][56][57][58][59][60][61][62] replica-exchange molecular dynamics (REMD), 63,64 accelerated molecular dynamics (aMD) [65][66][67][68][69] and Gaussian accelerated molecular dynamics (GaMD) 70-78 etc., have been proposed to probe conformational changes of receptors because of ligand bindings and residue mutations. Compared to cMD, MR-GaMD simulations can obtain more rational conformational sampling on receptors.…”

The design of compounds with desirable properties – The anti‐HIV case study

“…[3][4][5] From the perspective of the human immunodeficiency virus, the entity with the highest reported mutation rate, 6 it successfully fights continuous drug selective pressure, leading to the emergence of drug resistant forms. 7 Due to the absence of a successful anti-HIV vaccine and drawbacks of presently approved anti-HIV drugs, a design of a new drug candidates, with increased potency and less side effects (less toxic, increased pharmacokinetic properties) remains hot topic in scientific and pharmaceutical community, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] even 30 years after the first registered drug, azidothymidine. 25 Over the past 20 years, myriad of a quantitative structure-activity relationship (QSAR) studies were performed with the aim to design novel anti-HIV compounds.…”