Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding (original) (raw)
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Prediction of HIV integrase resistance mutation using in silico approaches
Infection, Genetics and Evolution, 2018
The Antiretroviral Therapy (ART) has been providing better treatment for the Human Immunodeficiency Virus 1 (HIV) infection, by reducing its viral load to undetectable levels and recovering the immune system. However, new HIV mutations could induce drug resistance to ART, increasing the viral load and disruption of immune system. One of these drugs is Dolutegravir (DTG), which inhibits HIV integrase (INT) activity. Our objective was to predict novel HIV mutations related to DTG resistance using in silico approaches in order to stablish a framework of searching for new HIV drug-resistant mutations. To this end, we modelled the INT structure and produced a mutational profile to investigate hotspots that may affect INT. Being the Y226K mutation the most frequent (0.3) and with a higher ΔΔG (+2.07), we selected to test the framework. To ratify the impact of Y226K, we docked the mutant INT with the DTG and compared the results with the Wild Type (WT) with known drug-resistant mutations. Moreover, we performed molecular dynamics simulations and calculated the binding energy along the time-course. When we compared the energies of the systems, the Y226K complex showed less binding affinity (ΔΔG=104.88) than the other mutated complexes compared with the WT, the Y226K complex showed even less binding affinity (ΔΔG=104.88). This variant somehow impedes the attachment of DTG to INT, indicating this mutant as possible resistance mutation.
Impact of Resistance Mutations on Inhibitor Binding to HIV‑1 Integrase
HIV-1 integrase (IN) is essential for HIV-1 replication, catalyzing two key reaction steps termed 3′ processing and strand transfer. Therefore, IN has become an important target for antiviral drug discovery. However, mutants have emerged, such as E92Q/N155H and G140S/Q148H, which confer resistance to raltegravir (RAL), the first IN strand transfer inhibitor (INSTI) approved by the FDA, and to the recently approved elvitegravir (EVG). To gain insights into the molecular mechanisms of ligand binding and drug resistance, we performed molecular dynamics (MD) simulations of homology models of the HIV-1 IN and four relevant mutants complexed with viral DNA and RAL. The results show that the structure and dynamics of the 140s' loop, comprising residues 140 to 149, are strongly influenced by the IN mutations. In the simulation of the G140S/Q148H double mutant, we observe spontaneous dissociation of RAL from the active site, followed by an intrahelical swing-back of the 3′-OH group of nucleotide A17, consistent with the experimental observation that the G140S/Q148H mutant exhibits the highest resistance to RAL compared to other IN mutants. An important hydrogen bond between residues 145 and 148 is present in the wild-type IN but not in the G140S/Q148H mutant, accounting for the structural and dynamical differences of the 140s' loop and ultimately impairing RAL binding in the double mutant. End-point free energy calculations that broadly capture the experimentally known RAL binding profiles elucidate the contributions of the 140s' loop to RAL binding free energies and suggest possible approaches to overcoming drug resistance.
The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral Integrase (IN) enzyme catalyses integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG) and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of Integrase Strand Transfer Inhibitors (INSTIs). In this study, we applied computational methods of molecular modelling and docking to analyse the effect of NOPs on the full-length IN structure and INSTI binding. We identified 16 NOPs within the Cameroonian derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any effect on INSTI binding. INSTIs displayed similar binding...
Journal of Molecular Biology, 2008
It has been shown that L-731988, a potent integrase inhibitor, targets a conformation of the integrase enzyme formed when complexed to viral DNA, with the 3′-end dinucleotide already cleaved. It has also been shown that diketo acid inhibitors bind to the strand transfer complex of integrase and are competitive with the host target DNA. However, published X-ray structures of HIV integrase do not include the DNA; thus, there is a need to develop a model representing the strand transfer complex. In this study, we have constructed an active-site model of the HIV-1 integrase complexed with viral DNA using the crystal structure of DNA-bound transposase and have identified a binding mode for inhibitors. This proposed binding mechanism for integrase inhibitors involves interaction with a specific Mg 2 + in the active site, accentuated by a hydrophobic interaction in a cavity formed by a flexible loop upon DNA binding. We further validated the integrase active-site model by selectively mutating key residues predicted to play an important role in the binding of inhibitors. Thus, we have a binding model that is applicable to a wide range of potent integrase inhibitors and is consistent with the available resistant mutation data.
In-silico simulation towards anti-HIV drug discovery: A tool in the hour of need
GERF Bulletin of Biosciences, 2011
Human immunodeficiency virus (HIV) is a constant threat to mankind due to its remarkable ability to mutate and develop resistance against anti-HIV agents. HIV integrase (HIV-IN) is a recently established therapeutic target for drug discovery. Absence of complete crystal structure of HIV-IN is a major hurdle to the progress of research towards development of therapeutic agents. Here we show how docking and dynamic simulation of HIV-IN can be employed to gain insight into the molecular interactions between HIV-IN and integrase strand transfer inhibitors (INSTIs). Further, it provides understanding about the crucial structural changes associated with INSTIs binding and resistance causing mutations. Such 3-D structural insight can further be utilized i) to design novel molecules and ii) also to overcome the development of resistance. Therefore, in absence of insight from experimental structural studies, use of computational approaches is a must to bridge the gap to bring significant progress in drug discovery.
Computational Analysis of Drug Design HIV-1 Integrase Target Protein
Human Journals. International Journal of Pharmacy and Pharmaceutical Research, 2023
Background: HIV-1 (Human Immuno Deficiency Virus) attacks the immune system and cannot treat which leads to AIDS (Acquired Immuno Deficiency Syndrome). HIV-1 integrates (IN) is a transfer inhibitor retroviral enzyme essential for the integration of genetic material into the DNA of the host cell and hence for viral replication. The absence of an equivalent enzyme in humans makes it an interesting target for anti-HIV drug design. Methods: The research aims to analyze the binding modes of SWISS-MODEL, H-DOCK, 3D-LIGAND SITE, and COMPUTATIONAL TOOLS. Swissmodel is a structural bioinformatics webserver dedicated to homology modeling 3D-protein structure. Docking computational simulation of a candidate ligand binding to a receptor is the process of classifying which ligands are mostly likely to interact favorably with a particular receptor based on the predicted free energy of binding. Docking assessment procedure to quantify the predictive capability of a docking protocol. Result: In biochemistry and molecular biology a binding site is a region of a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. This technology was using the further advances of drugs against Human Immuno Deficiency Virus-1. Conclusion: These results elucidate the basis for the inhibition of strand transfer and imply integrase-directed HIV-1 drug discovery efforts. Despite the availability of 25 anti-AIDS medications that have been licensed, there is still a need for the development of new therapies to treat AIDS for a variety of reasons, with the main one being the need for better resistance profiles.
Biophysical Journal, 2005
HIV-1 integrase (IN) is an essential enzyme for the viral replication and an interesting target for the design of new pharmaceuticals for multidrug therapy of AIDS. Single and multiple mutations of IN at residues T66, S153, or M154 confer degrees of resistance to several inhibitors that prevent the enzyme from performing its normal strand transfer activity. Four different conformations of IN were chosen from a prior molecular dynamics (MD) simulation on the modeled IN T66I/M154I catalytic core domain as starting points for additional MD studies. The aim of this article is to understand the dynamic features that may play roles in the catalytic activity of the double mutant enzyme in the absence of any inhibitor. Moreover, we want to verify the influence of using different starting points on the MD trajectories and associated dynamical properties. By comparison of the trajectories obtained from these MD simulations we have demonstrated that the starting point does not affect the conformational space explored by this protein and that the time of the simulation is long enough to achieve convergence for this system.