The Molecular Docking of Specific Reverse Transcriptase Inhibitory Ligands onto the Molecular Model of HIV-1 Reverse Transcriptase

Document Type : Original Article

Author

1 Behbahan Faculty of Medical Sciences, Behbahan, Iran

2 Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

Abstract

HIV-1 reverse transcriptase (RT) is a crucial enzyme in HIV replication and AIDS progression. It consists of p66 and p51 subunits and converts viral RNA into double-stranded DNA for integration into the host cell's genome. Managing HIV/AIDS depends on inhibiting HIV-1 RT, achieved through nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Understanding RT's structure, catalysis, inhibition, and resistance has been vital for disease management. To study the binding sites and interactions of reverse transcriptase inhibitors (RTIs) with HIV-1 RT, we utilized Molegro Virtual Docker for model preparation and docking. We also employed the SwissADME web tool for predicting physicochemical properties and pharmacokinetics of compounds of interest. We investigated the binding site and affinity of antiretroviral drugs, including delavirdine, tenofovir alafenamide, and atavirdine, with the HIV-1 RT enzyme. Additionally, we evaluated factors such as gastrointestinal absorption, blood-brain barrier penetration, Pgp substrate status, and skin permeability to assess the efficacy of these drugs in treating HIV/AIDS. The findings of this study may help us understand the interactions and potential applications of these compounds with other drugs, ultimately improving antiretroviral therapy for managing HIV-1 infection. Understanding the binding affinity, sites, and pharmacological properties of reverse transcriptase inhibitor compounds is crucial for developing effective antiretroviral therapies against HIV/AIDS.

Highlights

Roohallah Yousefi (Google Scholar)

Keywords

References

1.    Payagala S, Pozniak A. The global burden of HIV. Clin Dermatol. 2024 Mar-Apr;42(2):119-127. doi: 10.1016/j.clindermatol.2024.02.001. Epub 2024 Feb 21. PMID: 38387533..
2.    Panwar U, Chandra I, Selvaraj C, Singh SK. Current Computational Approaches for the Development of Anti-HIV Inhibitors: An Overview. Curr Pharm Des. 2019;25(31):3390-3405. doi: 10.2174/1381612825666190911160244. PMID: 31538884.
3.    Jonckheere H, Anné J, De Clercq E. The HIV-1 reverse transcription (RT) process as target for RT inhibitors. Med Res Rev. 2000 Mar;20(2):129-54. doi: 10.1002/(sici)1098-1128(200003)20:2<129::aid-med2>3.0.co;2-a. PMID: 10723025.
4.    Hu WS, Hughes SH. HIV-1 reverse transcription. Cold Spring Harb Perspect Med. 2012 Oct 1;2(10):a006882. doi: 10.1101/cshperspect.a006882. PMID: 23028129; PMCID: PMC3475395.
5.    Jochmans D. Novel HIV-1 reverse transcriptase inhibitors. Virus Res. 2008 Jun;134(1-2):171-85. doi: 10.1016/j.virusres.2008.01.003. Epub 2008 Mar 4. PMID: 18308412.
6.    Sarafianos SG, Marchand B, Das K, Himmel DM, Parniak MA, Hughes SH, Arnold E. Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol. 2009 Jan 23;385(3):693-713. doi: 10.1016/j.jmb.2008.10.071. Epub 2008 Nov 3. PMID: 19022262; PMCID: PMC2881421.
7.    Tachedjian G, Radzio J,  Sluis‐Cremer N. . Relationship between enzyme activity and dimeric structure of recombinant HIV‐1 reverse transcriptase. Proteins. 2005;60(1):5-13.
8.    Chiu TK, Davies DR. Structure and function of HIV-1 integrase. Curr Top Med Chem. 2004;4(9):965-77. doi: 10.2174/1568026043388547. PMID: 15134551.
9.    Himmel DM, Maegley KA, Pauly TA, Bauman JD, Das K, Dharia C, Clark AD Jr, Ryan K, Hickey MJ, Love RA, Hughes SH, Bergqvist S, Arnold E. Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site. Structure. 2009 Dec 9;17(12):1625-1635. doi: 10.1016/j.str.2009.09.016. PMID: 20004166; PMCID: PMC3365588.
10.    Esposito F, Corona A, Tramontano E. HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions. Mol Biol Int. 2012;2012:586401. doi: 10.1155/2012/586401. Epub 2012 Jun 20. PMID: 22778958; PMCID: PMC3388302.
11.    Gu SX, Zhu YY, Wang C, Wang HF, Liu GY, Cao S, Huang L. Recent discoveries in HIV-1 reverse transcriptase inhibitors. Curr Opin Pharmacol. 2020 Oct;54:166-172. doi: 10.1016/j.coph.2020.09.017. Epub 2020 Nov 8. PMID: 33176248.
12.    El Safadi Y, Vivet-Boudou V, Marquet R. HIV-1 reverse transcriptase inhibitors. Appl Microbiol Biotechnol. 2007 Jun;75(4):723-37. doi: 10.1007/s00253-007-0919-7. Epub 2007 Mar 17. PMID: 17370068.
13.    Spence RA, Kati WM, Anderson KS, Johnson KA. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science. 1995 Feb 17;267(5200):988-93. doi: 10.1126/science.7532321. PMID: 7532321; PMCID: PMC7526747.
14.    De Clercq E. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. Chem Biodivers. 2004 Jan;1(1):44-64. doi: 10.1002/cbdv.200490012. PMID: 17191775.
15.    De Clercq E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res. 1998 Jun;38(3):153-79. doi: 10.1016/s0166-3542(98)00025-4. PMID: 9754886.
16.    Wang Y, De Clercq E, Li G. Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment. Expert Opin Drug Metab Toxicol. 2019 Oct;15(10):813-829. doi: 10.1080/17425255.2019.1673367. Epub 2019 Oct 17. PMID: 31556749.
17.    Namasivayam V, Vanangamudi M, Kramer VG, Kurup S, Zhan P, Liu X, Kongsted J, Byrareddy SN. The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic. J Med Chem. 2019 May 23;62(10):4851-4883. doi: 10.1021/acs.jmedchem.8b00843. Epub 2018 Dec 27. PMID: 30516990; PMCID: PMC7049092.
18.    Zhuang C, Pannecouque C, De Clercq E, Chen F. Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years. Acta Pharm Sin B. 2020 Jun;10(6):961-978. doi: 10.1016/j.apsb.2019.11.010. Epub 2019 Nov 21. PMID: 32642405; PMCID: PMC7332669.
19.    Das K, Martinez SE, Arnold E. Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance. Antimicrob Agents Chemother. 2017 May 24;61(6):e00224-17. doi: 10.1128/AAC.00224-17. PMID: 28396546; PMCID: PMC5444136.‏
20.    Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH. PubChem Substance and Compound databases. Nucleic Acids Res. 2016 Jan 4;44(D1):D1202-13. doi: 10.1093/nar/gkv951. Epub 2015 Sep 22. PMID: 26400175; PMCID: PMC4702940.
21.    Bitencourt-Ferreira G, de Azevedo WF Jr. Molegro Virtual Docker for Docking. Methods Mol Biol. 2019;2053:149-167. doi: 10.1007/978-1-4939-9752-7_10. PMID: 31452104.
22.    Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717. doi: 10.1038/srep42717. PMID: 28256516; PMCID: PMC5335600.
23.    Daina A, Michielin O, Zoete V. iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model. 2014 Dec 22;54(12):3284-301. doi: 10.1021/ci500467k. Epub 2014 Nov 25. PMID: 25382374.
24.    Daina, A., & Zoete, V. (2016). A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem, 11(11), 1117-1121.‏
25.    Yousefi, R. Molecular Docking Study of Rosmarinic Acid and Its Analog Compounds on Sickle Cell Hemoglobin. Eurasian J Sci Technol.2024;4(4):303-330. doi: 10.48309/ejst.2024.444334.1130.‏
26.    Yousefi R. The Potential Application of Roselle Extracts (Hibiscus sabdariffa L.) in Managing Diabetes Mellitus. J Adv Pharm Res. 2024; 8(2):38-48. doi: 10.21608/aprh.2024.277267.1260
27.    Yousefi R. Binding of curcumin near the GBT440 binding site at the alpha cleft in the sickle cell hemoglobin model [Pdb ID: 1NEJ]. J Adv Biomed & Pharm Sci.2024;7(2):70-74.
28.    Powell MD, Beard WA, Bebenek K, Howard KJ, Le Grice SF, Darden TA, Kunkel TA, Wilson SH, Levin JG. Residues in the alphaH and alphaI helices of the HIV-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer. J Biol Chem. 1999 Jul 9;274(28):19885-93. doi: 10.1074/jbc.274.28.19885. PMID: 10391934.
29.    Titmuss SJ, Keller PA, Griffith R. Docking experiments in the flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase. Bioorg Med Chem. 1999 Jun;7(6):1163-70. doi: 10.1016/s0968-0896(99)00012-7. PMID: 10428388.
30.    Svarovskaia ES, Cheslock SR, Zhang WH, Hu WS, Pathak VK. Retroviral mutation rates and reverse transcriptase fidelity. Front Biosci. 2003 Jan 1;8:d117-34. doi: 10.2741/957. PMID: 12456349.
31.    Shafer RW, Rhee SY, Pillay D, Miller V, Sandstrom P, Schapiro JM, Kuritzkes DR, Bennett D. HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS. 2007 Jan 11;21(2):215-23. doi: 10.1097/QAD.0b013e328011e691. PMID: 17197813; PMCID: PMC2573394.
32.    Kellam P, Boucher CA, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1934-8. doi: 10.1073/pnas.89.5.1934. PMID: 1371886; PMCID: PMC48568.
Trends in Pharmaceutical Sciences
Volume 10, Issue 2
June 2024
Pages 91-112

Files

Share

How to cite

Statistics