Computational Analysis of Drug Design HIV-1 Integrase Target Protein (original) (raw)
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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...
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.
Molecular Modelling and QSAR in the Discovery of HIV1 Integrase Inhibitors
Current Computer - Aided Drug Design, 2007
The treatment regimens for the HIV-1 have mainly included reverse transcriptase or protease inhibitors but their long-term clinical utility is limited by severe side effects and viral drug resistance. A new attractive target for chemotherapeutic intervention can be the Integrase enzyme, that mediates the integration of HIV-1 DNA into a host chromosome, for which there is no known counterparts in the host cell. A number of derivatives have been found to inhibit IN in in vitro assays, but no successful drug based on them has emerged so far, although many compounds have been proposed. Moreover most of the inhibitors do not belong to a very precise structural class: this fact makes these compounds a suitable target to be approached by all QSAR methods (classical and 3D) which therefore have been used to study the IN inhibitors. This review focuses on the molecular basis and rationale for developing integrase inhibitors and assesses the literature results of the chemometric study on classes of these inhibitors. Rational drug design by mean of the pharmacophore approach, rigid and flexible docking methods, and de novo design contributed to the identification of the most promising class of inhibitors, the DKAs. Moreover molecular dynamics studies were included since they can contribute to give further insight into the inhibitors binding modes already explored by means of the docking simulations.
Journal of the Serbian Chemical Society, 2019
Acquired immunodeficiency syndrome (AIDS) is a significant human health threat around the world and therefore, the study of anti-HIV drug design has become an important task for today's society. In this paper, a three-dimensional quantitative structure-activity relationships study (3D-QSAR) was conducted on 72 HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using Topomer comparative molecular field analysis (Topomer CoMFA). The multiple correlation coefficients of fitting, cross-validation, and external validation were 0.899, 0.788 and 0.942, respectively. The results indicated that the obtained model had both a favorable estimation stability and a good prediction capability. Topomer Search was used to search appropriate R groups from the ZINC database, Thereby, 14 new compounds were designed, and 12 of the new compounds were predicted to be more active than the template molecule. These results strongly suggest that the Topomer search was effective in screening and could be a useful guide in the design of new HIV-1 drugs. The ligands of the template molecule and the new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor. The results showed that the ligands would generally form hydrogen-bonding interactions with the residues Ala28, Asp29, Gly49 and Ile50 of the protein receptor, thereby providing additional insights for the designing of even more effective drugs.
Iraqi Journal of Pharmaceutical Sciences ( P-ISSN 1683 - 3597 E-ISSN 2521 - 3512)
Flexible molecular docking is a computational method of structure-based drug design to evaluate binding interactions between receptor and ligand and identify the ligand conformation within the receptor pocket. Currently, various molecular docking programs are extensively applied; therefore, realizing accuracy and performance of the various docking programs could have a significant value. In this comparative study, the performance and accuracy of three widely used non-commercial docking software (AutoDock Vina, 1-Click Docking, and UCSF DOCK) was evaluated through investigations of the predicted binding affinity and binding conformation of the same set of small molecules (HIV-1 protease inhibitors) and a protein target HIV-1 protease enzyme. The tested sets are composed of eight receptor-ligand complexes with high resolution crystal structures downloaded from Protein Data Bank website. Molecular dockings were applied between approved HIV-1 protease inhibitors and the HIV-1 protease u...
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.
Prediction of the interaction of HIV-I Integrase and Raltegravir through molecular modeling approach
Journal of Pharmacy Research
The present study was designed to investigate the binding mode of the drug Raltegravir with the newly modeled protein HIV-I integrase. The 3-D structure model of HIV-I integrase was constructed from the putative sequence using homology modeling techniques. Target sequence possessed sequence identity 80.181% with the template. Structural refinement and energy minimization of the built HIV-I integrase model was done. The structural quality and accuracy of the predicted model was verified using Procheck, WHAT IF, Errat and Verify 3D showed that the modeled structure is satisfactory and suited for analysis of the substrate binding pocket and docking studies. Validity of the structural model was assessed by docking simulation with the HIV-I integrase inhibitor Raltegravir. Detailed analyses of HIV-I integrase and Raltegravir interactions were done in Molsoft ICM-pro 3.5. Based on the RMSD and energy values, the best docking orientation was selected. The residues in binding domain responsible for binding to the inhibitor with high binding affinity were identified.