Drug Properties and Drug Ligand-Binding Comparison Analysis on Tenofovir and Zidovudine as a Reverse Transcriptase Inhibitor of HIV-1
Keywords:HIV-1, reverse transcriptase (RT), binding affinity, molecular docking, ADMET
Objective: The human immunodeficiency virus (HIV) infection has been a public health concern with no available cure. It is recommended for HIV patients to be supplied with antiretroviral therapy (ART) as their lifelong treatment to help reduce the course of this disease. This paper utilized bioinformatics approaches to examine tenofovir and zidovudine as an inhibitor of reverse transcriptase (RT) enzyme in HIV-1.
Material and methods: The 3D Model of the RT enzyme was generated using Swiss-Model Expasy from the FASTA amino acid sequence obtained from Protein Data Bank (PDB). The enzyme then went through several modifications using PyMOL before inserting them into CASTp: Computed Atlas of Surface Topography of Proteins active site prediction software, as well as PyRx (Python Prescription Virtual Screening Tool) and BIOVIA Discovery Studio 2021 for molecular docking. PreADMET analysis was used to determine the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the two drugs.
Results: The results from molecular docking revealed that tenofovir possessed higher binding affinity towards HIV-1 RT rather than zidovudine. ADMET analysis showed that tenofovir have better Pgp-inhibitor absorption and blood brain barrier (BBB) distribution than zidovudine. Meanwhile, zidovudine possessed higher Fu with carcinogenic properties.
Conclusion: Both drugs exhibited poor at Caco-2 absorption with high passive MDCK permeability, tested positive for human intestinal absorption (HIA), have up to 30% bioavailability, proper plasma protein binding (PPB) and volume distribution (VD), may act as both CYP substrate and inhibitor, have moderate clearance (CL), long half-life (T½), and possessed different toxicity and allergic properties.
Seitz R. Human immunodeficiency virus (HIV). Transfusion Medicine And Hemotherapy 2016; 43: 203-222.
Waymack JR, Sundareshan V. Acquired Immune Deficiency Syndrome. United States: Treasure Island (FL): StatPearls Publishing; 2021.
Vidya Vijayan KK, Karthigeyan KP, Tripathi SP, Hanna LE. Pathophysiology of CD4+ T-cell depletion in HIV-1 and HIV-2 infections. Frontiers In Immunology 2017; 8: 580.
Hu WS, Hughes SH. HIV-1 reverse transcription. Cold Spring Harb Perspect Med 2012 ;2: a006882.
Arts, EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harbor Perspectives in Medicine 2012; 2: a007161.
Lewin S, Evans V, Elliott J, Spire B, Chomont N. Finding a cure for HIV: will it ever be achievable?. Journal of the International AIDS Society 2011; 14: 4-4.
Holtz CM, Mansky LM. Variation of HIV-1 mutation spectra among cell types. Journal of Virology 2013; 87: 5296–5299.
Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate. Clinical Pharmacokinetics 2004; 43: 595–612.
Lyseng-Williamson KA, Reynolds NA, Plosker GL. Tenofovir disoproxil fumarate. Drugs 2005; 65: 413–432.
Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. Drugbank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 2006; 1: 34 (Database issue): D668-72. 16381955.
Binkowski TA, Naghibzadeh S, Liang J. CASTp: Computed Atlas of Surface Topography of proteins. Nucleic Acids Res 2003; 31: 3352-5.
Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol 2015; 1263: 243-50.
Anderson PL, Rower JE. Zidovudine and lamivudine for HIV infection. Clinical Medicine Reviews in Therapeutics 2010; 2: a2004.
Tsibris AM, Hirsch MS. Antiretroviral therapy for human immunodeficiency virus infection. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Philadepihia: WB Saunders; 2015.p.1622-1641.
HIV data and statistics [Internet]. Who.int. 2021 [cited 20 July 2022]. Available from: https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/strategic-information/hiv-data-and-statistics.
Guan L, Yang H, Cai Y, Sun L, Di P, Li W, Tang Y. ADMET-score–a comprehensive scoring function for evaluation of chemical drug-likeness. Medchemcomm 2019; 10: 148-157.
Hubatsch I, Ragnarsson E, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nature Protocols 2007; 2: 2111-2119.
Arthur J. The MDCK cell line is made up of populations of cells with diverse resistive and transport properties. Tissue And Cell 2000; 32: 446-450.
Jin X, Luong T, Reese N, Gaona H, Collazo-Velez V, Vuong, C. Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations. Journal Of Pharmacological And Toxicological Methods 2014; 70:, 188-194.
Amin M. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 2013; 7: DTI.S12519.
Yan A, Wang Z, Cai Z. Prediction of human intestinal absorption by GA feature selection and support vector machine regression. International Journal Of Molecular Sciences 2008; 9: 1961-1976.
Bitew M, Desalegn T, Demissie T, Belayneh A, Endale M, Eswaramoorthy R. Pharmacokinetics and drug-likeness of antidiabetic flavonoids: Molecular docking and DFT study. PLOS ONE 2021; 16: e0260853.
Kumar R, Sharma A, Varadwaj PK. A prediction model for oral bioavailability of drugs using physicochemical properties by support vector machine. J Nat Sci Biol Med 2011 Jul; 2:168-73.
Trainor GL. The importance of plasma protein binding in drug discovery. Expert Opinion on Drug Discovery 2007; 2: 51-64.
Smith DA, Beaumont K, Maurer TS, Di L. Volume of distribution in drug design: Miniperspective. Journal of Medicinal Chemistry 2015; 58: 691-5698.
Daneman R, Prat A. The blood–brain barrier. Cold Spring Harbor Perspectives in Biology 2015; 7.
Helliwell M, Zhang Y, El Harchi A, Du C, Hancox J, Dempsey C. Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker. Journal Of Biological Chemistry 2018; 293 7040-7057.
Sanguinetti M, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006; 440: 463-469.
David, S., & Hamilton, J. P. Drug-induced Liver Injury. US gastroenterology & hepatology review 2010; 6: 73–80.
National Institutes of Health. LiverTox: Clinical and Research Information on Drug- Induced Liver Injury [Internet]. National Center for Biotechnology Information 2012.
Maloy E, Follmann W, Degen G, Oesch F, Hengstler J. Brenner's Encyclopedia of Genetics (Second Edition. Cambridge: Academic Press; 2013.p.104-107.
Dong J, Wang NN, Yao ZJ, Zhang L, Cheng Y, Ouyang D, Cao DS. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. Journal of Cheminformatics; 2018 10: 1-11.
Saganuwan, S. Toxicity studies of drugs and chemicals in animals: an overview. Bulgarian Journal Of Veterinary Medicine 2017; 20: 291-318.
Basketter D, Darlenski R, Fluhr J. Skin irritation and sensitization: Mechanisms and new approaches for risk assessment. Skin Pharmacology And Physiology 2008; 21: 191-202.
Nisius B, Sha F, Gohlke H. Structure-based computational analysis of protein binding sites for function and druggability prediction. Journal of Biotechnology 2012; 159: 123–134.
Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Current Computer-Aided Drug Design 2011; 7: 146–157.
Salahudeen MS, Nishtala P S. An overview of pharmacodynamic modelling, ligand-binding approach and its application in clinical practice. The Official Publication of the Saudi Pharmaceutical Society 2017; 25: 165–175.
Schweiker S, Levonis S. Navigating the intricacies of molecular docking. Future Medicinal Chemistry 2020; 12: 469-471.
Chen D, Oezguen N, Urvil P, Ferguson C, Dann SM, Savidge TC. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Science Advances 2016; 2: e1501240.
Abelian A, Dybek M, Wallach J, Gaye B, Adejare A. Pharmaceutical chemistry. Remington 2021: 105-128.
Frey P. Low-Barrier hydrogen bonds. Encyclopedia Of Biological Chemistry 2013: 756-759.
Kalbaugh TL, VanDongen HM, VanDongen AM. Ligand-binding residues integrate affinity and efficacy in the NMDA receptor. Molecular Pharmacology 2004; 66: 209–219.
Velen K, Lewis JJ, Charalambous S, Grant AD, Churchyard GJ, Hoffmann CJ. Comparison of tenofovir, zidovudine, or stavudine as part of first-line antiretroviral therapy in a resource-limited-setting: a cohort study. PloS One 2013; 8: e64459.
Ayele T, Jarso H, Mamo G. Immunological outcomes of Tenofovir versus Zidovudine-based regimens among people living with HIV/AIDS: a two years retrospective cohort study. AIDS Res Ther 2017; 14: 5.
Cheung C, Lai W, Shuter J. Zidovudine- versus tenofovir-Based antiretroviral therapy for the initial treatment of HIV infection in the ethnic minority region of Liangshan Prefecture, Sichuan Province, China. Journal Of The International Association Of Providers Of AIDS Care (JIAPAC) 2017; 16: 189-193.
Sacan A, Ekins S, Kortagere S. Applications and limitations of In silico models in drug discovery. methods in molecular biology 2012: 87-124.
Sethi A, Joshi K, Sasikala K, Alvala M. Molecular docking in modern drug discovery: Principles and recent applications. Drug Discovery And Development - New Advances.
Copyright (c) 2023 Olivia Putri, Nicholas Dustin, Alfa Aprilio Sengkey, Jayson Dolor, Melinda Christian, Rosemarie Angelica, Sanny Sanny, Arli Aditya Parikesit
This work is licensed under a Creative Commons Attribution 4.0 International License.