Docking Study of HIV-1 Reverse Transcriptase (HIV-1 RT) with Well-Known Nucleoside Reverse Transcriptase Inhibitors (NRTIs (original) (raw)
Related papers
HIV-Reverse Transcriptase Inhibition: Inclusion of Ligand-Induced Fit by Cross-Docking Studies
Journal of Medicinal Chemistry, 2005
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), a definitive role in the treatment of HIV-1 infections. Since the appearance of HEPT and TIBO, more than 30 structurally different classes of compounds have been reported as NNRTIs, which are specific inhibitors of HIV-1 replication, targeting the HIV-1 reverse transcriptase (RT). Nevirapine and delavirdine are the first formally licensed for clinical use, and others have been licensed afterward, while several are in preclinical or clinical development. The NNRTIs interact with a specific site of HIV-1 RT (nonnucleoside binding site, NNBS) that is close to, but distinct from, the NRTI binding site. In this work we report the application of the Autodock program assessing its usability through reproduction of 41 NNRTI experimental bound conformations. Moreover, cross-docking experiments on the wild-type and mutated RT forms were conducted to take into account the enzyme flexibility as a valuable tool for structure-based drug design (SBDD) studies and to gain insight on the mode of action of new anti-HIV agents active against both wild-type and resistant strains.
Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors
Chemical Biology & Drug Design, 2023
Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).
Journal of Chemical Information and Modeling, 2007
A virtual screening protocol has been applied to seek non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) and its K103N mutant. First, a chemical similarity search on the Maybridge library was performed using known NNRTIs as reference structures. The top-ranked molecules obtained from this procedure plus 26 known NNRTIs were then docked into the binding sites of the wild-type reverse transcriptase (HIV-RT) and its K103N variant (K103N-RT) using Glide 3.5. The top-ranked 100 compounds from the docking for both proteins were post-scored with a procedure using molecular mechanics and continuum solvation (MM-GB/SA). The validity of the virtual screening protocol was supported by (i) testing of the MM-GB/SA procedure, (ii) agreement between predicted and crystallographic binding poses, (iii) recovery of known potent NNRTIs at the top of both rankings, and (iv) identification of top-scoring library compounds that are close in structure to recently reported NNRTI HTS-hits. However, purchase and assaying of selected top-scoring compounds from the library failed to yield active anti-HIV agents. Nevertheless, the highest-ranked database compound, S10087, was pursued as containing a potentially viable core. Subsequent synthesis and assaying of S10087 analogs proposed by further computational analysis yielded anti-HIV agents with EC 50 values as low as 310 nM. Thus, with the aid of computational tools, it was possible to evolve a false positive into a true active.
Proteins: Structure, Function, and Genetics, 2002
The docking of small molecules to proteins has played an important role in the understanding of drug/receptor interactions. An important drug/receptor interaction is between nonnucleoside inhibitors of HIV-1 RT and the nonnucleoside binding pocket. We report the results of docking calculations in which we have docked known and proposed non-nucleoside reverse transcriptase inhibitors to the type 1 virus. The proposed NNRTIs dock in a similar position and orientation as known inhibitors. In addition, we observe a linear correlation between the calculated interaction energy and EC50 for the inhibitors, suggesting that the docked structure orientation and the interaction energies are reasonable. Two hydrogen bonds between nevirapine and RT (3HVT and 1VRT) are observed and are reproduced across different docking schemes. Since we used two different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different levels of resolution (2.9 and 2.2 Å , respectively), we propose that structures with resolutions better than 3 Å can be used to produce reasonable docking results.
Bioinformation, 2012
The study of Human immunodeficiency virus (HIV) in humans and animal models in last 31 years suggested that it is a causative agent of AIDS. This causes serious pandemic public health concern globally. It was reported that the HIV-1 reverse transcriptase (RT) played a critical role in the life cycle of HIV. Therefore, inhibition of HIV-1RT enzyme is one of the major and potential targets in the treatment of AIDS. The enzyme (HIV-1RT) was successfully targeted by non nucleotide reverse transcriptase inhibitors (NNRTIs). But frequent application of NNRTIs led drug resistance mutation on HIV infections. Therefore, there is a need to search new NNRTIs with appropriate pharmacophores. For the purpose, a virtually screened 3D model of unliganded HIV-1RT (1DLO) was explored. The unliganded HIV-1RT (1DLO) was docked with 4-thiazolidinone and its derivatives (ChemBank Database) by using AutoDock4. The best seven docking solutions complex were selected and analyzed by Ligplot. The analysis showed that derivative (5E)-3-(2-aminoethyl)-5-(2-thienylmethylene)-1, 3-thiazolidine-2, 4-dione (CID 3087795) has maximum potential against unliganded HIV-1RT (1DLO). The analysis was done on the basis of scoring and binding ability. The derivative (5E)-3-(2aminoethyl)-5-(2-thienylmethylene)-1, 3-thiazolidine-2, 4-dione (CID 3087795) indicated minimum energy score and highest number of interactions with active site residue and could be a promising inhibitor for HIV-1 RT as Drug target.
Chemical Biology & Drug Design, 2008
We have performed the docking of sulfonyl hydrazides complexed with cytosolic branched-chain amino acid aminotransferase (BCATc) to study the orientations and preferred active conformations of these inhibitors. The study was conducted on a selected set of 20 compounds with variation in structure and activity. In addition, the predicted inhibitor concentration (IC 50 ) of the sulfonyl hydrazides as BCAT inhibitors were obtained by a quantitative structure-activity relationship (QSAR) method using three-dimensional (3D) vectors. We found that three-dimensional molecule representation of structures based on electron diffraction (3D-MoRSE) scheme contains the most relevant information related to the studied activity. The statistical parameters [cross-validate correlation coefficient (Q 2 = 0.796) and fitted correlation coefficient (R 2 = 0.899)] validated the quality of the 3D-MoRSE predictive model for 16 compounds. Additionally, this model adequately predicted four compounds that were not included in the training set.
Chemical Biology & Drug Design, 2009
Reverse transcriptase, being the pivot in human immunodeficiency virus replication, is one of the most attractive targets for the development of new antiretroviral agents. We applied a virtual screening workflow based on a combination of physicochemical filters with high-throughput rigid molecular docking to discover novel efficient lead scaffolds for human immunodeficiency virus type 1 reverse transcriptase inhibition. In our protocol, different filters were employed to enrich the leadlikeness and improve the ligands efficiency of the filtered compounds. Out of the 238 819 compounds included in the Natinal Cancer Institute database, 500 virtual screening hits were retrieved employing FILTER and FRED (molecular docking engine) softwares. Four compounds from the 20 highest ranking scored hits tested positive in human immunodeficiency virus type 1 reverse transcriptase using non-radioactive colorimetric assay method. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for human immunodeficiency virus type 1 reverse transcriptase inhibition that could be useful for drug development in the area of acquired immune-deficiency syndrome treatment.
Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review
Molecules (Basel, Switzerland), 2018
Currently, millions of people are living with human immunodeficiency virus type 1 (HIV-1), which causes acquired immunodeficiency syndrome. However, the spread of the HIV-1 resistance to antiviral agents is the major problem in the antiretroviral therapy and medical management of HIV-infected patients. HIV-1 reverse transcriptase (RT) is one of the key viral targets for HIV-1 inhibition. Therefore, the studies on the combatting the HIV resistance that occurs due to the structural changes in RT, are in great demand. This work aims to provide an overview of the state-of-the-art molecular docking approaches applied to the studies of the HIV-1 resistance, associated with RT structure changes. We have reviewed recent studies using molecular docking with mutant forms of RT. The work discusses the modifications of molecular docking, which have been developed to find the novel molecules active against resistance mutants of RT and/or recombinant strains of HIV-1. The perspectives of the exis...
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are structurally diverse group of compounds which binds to reverse transcriptase (RT) enzyme of Human Immunodeficiency Virus (HIV). Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. Therefore, attempts have been made to discover the NNRTIs active against both drug sensitive, as well as drug resistant strains of HIV-1 RT. In the present study, using structure-based virtual screening online database of small molecules was screened against wild strain of HIV-1 RT. Among the screened ligands, top thirty hits which exhibited lowest G score against wild HIV RT were further evaluated against two clinically drug resistance strains of HIV-1 RT. Docking study of these top thirty hits revealed that around nine ligands exhibited significant binding affinity (G score less than-10) against wild, as well as two drug resistance strains of HIV-1 RT. These nine compounds were further selected for in silico prediction of physiochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters using QikProp module of Schrödinger and online tool admetSAR.
Background and aim: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are structurally diverse group of compounds which binds to Reverse Transcriptase (RT) enzyme of Human Immunodeficiency Virus (HIV). Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. Therefore, attempts have been made to develop NNRTIs active against both drug sensitive as well as drug resistant strains of HIV-1 RT. Method: Five novel series of Tetrahydroquinoline derivatives were designed as Non-Nucleoside inhibitors of HIV-1 RT based on the pharmacophoric requirements. In-Silico docking studies of the designed analogues were performed against both drug sensitive and resistant strains of HIV-1 RT. Standard drug rilpivirine, etravirine and efavirenz were used for the purpose of docking validation and comparison. Results and discussion: Among the designed analogs, four compounds (2x, 3x, 3f and 5t) showed significant in-silico activity against all three variants of HIV-1 RT. These four compounds were further selected for in-silico prediction of absorption, distribution, metabolism, excretion and toxicity using Quick-pro module of Schrodinger and online tool AdmetSAR respectively. Conclusion: Based on the results of in-silico docking studies and ADMET properties, four compounds (2x, 3x, 3f and 5t) were identified as lead molecules for further development of novel anti-HIV agents active against both wild-type and drug resistant strains with better therapeutic profile. Predicted ADMET properties of these four designed analogues were within the acceptable range of druggable properties.