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Multiple-receptor conformation docking, dock pose clustering, and 3D QSAR-driven approaches exploring new HIV-1 RT inhibitors

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Abstract

Human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) plays a key in the life cycle of HIV-1. It is considered to be one of the promising targets for treating HIV/AIDS which contains two drug binding sites, a substrate binding site, and an allosteric site. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of RT inhibitors that bind to allosteric sites on HIV-1 RT in a non-competitive manner and thereby disrupting the conformation of RT. Hence, they can act as potent inhibitors against HIV-1 RT. In present study, the key structural requirements for enhancing HIV-1 RT inhibitory activity were explored from combined docking and three-dimensional quantitative structure activity relationship (3D QSAR) protocols. Initially, multiple-receptor conformation docking (MRCD) was performed using a series of diaryl pyridine and pyrimidine derivatives into the active site of ten X-ray crystal structures and one NMR-resolved conformation of HIV-1 RT. Later, the dock poses obtained from docking were clustered and 3D QSAR models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Finally, a robust model was established using cross-validation techniques and the robustness of the model was confirmed through high accuracy of q2loo of 0.843 and 0.682, r2ncv of 0.977 and 0.949, and r2pred of 0.702 and 0.690, respectively, for CoMFA and CoMSIA. Based on the outcome of the results, new pyrimidine derivatives having potential inhibitory against HIV-1 RT were designed.

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References

  1. Sergeyev S, Yadav AK, Franck P, Michiels J, Lewi P, Heeres J, Vanham G, Arien KK, Christophe ML, Velde V, De Winter H, Maes BUW (2016) 2,6-Di(arylamino)-3-fluoropyridine derivatives as HIV non-nucleoside reverse transcriptase inhibitors. J Med Chem 59:1854–1868

    Article  CAS  PubMed  Google Scholar 

  2. Jochmans D (2008) Novel HIV-1 reverse transcriptase inhibitors. Virus Res 134:171–185

    Article  CAS  PubMed  Google Scholar 

  3. De Corte BL (2005) From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Med Chem 48:1689–1696

    Article  CAS  PubMed  Google Scholar 

  4. Pauwels R (2004) New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections. Curr Opin Pharmacol 4:437–446

    Article  CAS  PubMed  Google Scholar 

  5. Tantillo C, Ding J, Jacobo-Molina A, Nanni RG, Boyer PL, Hughes SH, Pauwels R, Andries K, Janssen PA, Arnold E (1994) Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase: Implications for mechanisms of drug inhibition and resistance. x 243:369–387

    CAS  Google Scholar 

  6. Bec G, Meyer B, Gerard MA, Steger J, Fauster K, Wolff P, Burnouf D, Micura R, Dumas P, Ennifar E (2013) Thermodynamics of HIV-1 reverse transcriptase in action elucidates the mechanism of action of non-nucleoside inhibitors. J Am Chem Soc 135:9743–9752

    Article  CAS  PubMed  Google Scholar 

  7. Xia Q, Radzio J, Anderson KS, Sluis-Cremer N (2007) Probing non-nucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses. Protein Sci 16:1728–1737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Martins S, Ramos MJ, Fernandes PA (2008) The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection. Curr Med Chem 15:1083–1095

    Article  CAS  PubMed  Google Scholar 

  9. Das K, Clark AD, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E (2004) Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 47:2550–2560

    Article  CAS  PubMed  Google Scholar 

  10. Dueweke TJ, Poppe SM, Romero DL, Swaney SM, So AG, Downey KM, Althaus IW, Reusser F, Busso M, Resnick L (1993) U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother 37:1127–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Young SD, Britcher SF, Tran LO, Payne LS, Lumma WC, Lyle TA, Huff JR, Anderson PS, Olsen DB, Carroll SS (1995) L-743, 726 (DMP-266): a novel, highly potent non-nucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 39:2602–2605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Azijn H, Tirry I, Vingerhoets J, de Bethune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT (2010) TMC278, a next generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 54:718–727

    Article  CAS  PubMed  Google Scholar 

  13. Chen X, Zhan P, Li D, De Clercq E, Liu X (2011) Recent advances in DAPYs and related analogues as HIV-1 NNRTIs. Curr Med Chem 18:359–376

    Article  CAS  PubMed  Google Scholar 

  14. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S (1985) 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci 82:7096–7100

    Article  CAS  PubMed  Google Scholar 

  15. Zhan P, Pannecouque C, De Clercq E, Liu X (2016) Anti-HIV drug discovery and development: current innovations and future trends. J Med Chem 59:2849–2878

    Article  CAS  PubMed  Google Scholar 

  16. Schöller-Gyüre M, Kakuda TN, De Smedt G, Vanaken H, Bouche MP, Peeters M, Woodfall B, Hoetelmans RM (2008) A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers. Br J Clin Pharmacol 66:508–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Seminari E, Castagna A, Lazzarin A (2008) Etravirine for the treatment of HIV infection. Expert Rev Anti-Infect Ther 6:427–433

    Article  CAS  PubMed  Google Scholar 

  18. Fatima S, Jatavath MB, Bathini R, Sivan SK, Manga V (2014) Multiple receptor conformation docking, dock pose clustering and 3D QSAR studies on human poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors. J Recept Signal Transduct Res 34:417–430

    Article  CAS  PubMed  Google Scholar 

  19. Peddi SR, Sivan SK, Manga V (2016) An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors. J Recept Signal Transduct Res 36:488–504

    Article  CAS  PubMed  Google Scholar 

  20. Sivan SK, Manga V (2012) Multiple receptor conformation docking and dock pose clustering as tool for CoMFA and CoMSIA analysis—a case study on HIV-1 protease inhibitors. J Mol Model 18:569–582

    Article  CAS  PubMed  Google Scholar 

  21. Chong P, Sebahar P, Youngman M, Garrido D, Zhang H, Stewart EL, Nolte RT, Wang L, Ferris RG, Edelstein M, Weaver K, Mathis A, Peat A (2012) Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Med Chem 55:10601–10609

    Article  CAS  PubMed  Google Scholar 

  22. Cote B, Burch JD, Asante-Appiah E, Bayly C, Bedard L, Blouin M, Campeau LC, Cauchon E, Chan M, Chefson A, Coulombe N, Cromlish W, Debnath S, Deschenes D, Dupont-Gaudet K, Falgueyret JP, Forget R, Gagne S, Gauvreau D, Girardin M, Guiral S, Langlois E, Li CS, Nguyen N, Papp R, Plamondon S, Roy A, Roy S, Seliniotakis R, St-Onge M, Ouellet S, Tawa P, Truchon JF, Vacca J, Wrona M, Yan Y, Ducharme Y (2014) Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses. Bioorg Med Chem Lett 24:917–922

    Article  CAS  PubMed  Google Scholar 

  23. Gomez R, Jolly SJ, Williams T, Vacca JP, Torrent M, McGaughey G, Lai MT, Felock P, Munshi V, Distefano D, Flynn J, Miller M, Yan Y, Reid J, Sanchez R, Liang Y, Paton B, Wan BL, Anthony N (2011) Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase. J Med Chem 54:7920–7933

    Article  CAS  PubMed  Google Scholar 

  24. Kertesz DJ, Brotherton-Pleiss C, Yang M, Wang Z, Lin X, Qiu Z, Hirschfeld DR, Gleason S, Mirzadegan T, Dunten PW, Harris SF, Villasenor AG, Hang JQ, Heilek GM, Klumpp K (2010) Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. Bioorg Med Chem Lett 20:4215–4218

    Article  CAS  PubMed  Google Scholar 

  25. Lansdon EB, Brendza KM, Hung M, Wang R, Mukund S, Jin D, Birkus G, Kutty N, Liu X (2010) Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design. J Med Chem 53:4295–4299

    Article  CAS  PubMed  Google Scholar 

  26. Laplante SR, Bilodeau F, Aubry N, Gillard JR, O’Meara J, Coulombe R (2013) N- versus O-alkylation: utilizing NMR methods to establish reliable primary structure determinations for drug discovery. Bioorg Med Chem Lett 23:4663–4668

    Article  CAS  PubMed  Google Scholar 

  27. Parrish J, Tong L, Wang M, Chen X, Lansdon EB, Cannizzaro C, Zheng X, Desai MC, Xu L (2013) Synthesis and biological evaluation of phosphonate analogues of nevirapine. Bioorg Med Chem Lett 23:1493–1497

    Article  CAS  PubMed  Google Scholar 

  28. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw ED, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749

    Article  CAS  Google Scholar 

  29. Wang L, Tian Y, Chen W, Liu H, Zhan P, Li D, Liu H, De Clercq E, Pannecouque C, Liu X (2014) Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: discovery of novel [1,2,4] triazolo[1,5-a] pyrimidines using a structure-guided core-refining approach. Eur J Med Chem 85:293–303

    Article  CAS  PubMed  Google Scholar 

  30. Wan Z, Yao J, Tao Y, Mao T, Wang X, Lu Y, Wang H, Yin H, Wu Y, Chen F, De Clercq E, Daelemans D (2015) Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem 97:1–9

    Article  CAS  PubMed  Google Scholar 

  31. Yang J, Chen W, Kang D, Lu X, Li X, Liu Z, Huang B, Daelemans D, Pannecouque C, De Clercq E, Zhan P, Liu X (2016) Design, synthesis and anti-HIV evaluation of novel diarylpyridine derivatives targeting the entrance channel of NNRTI binding pocket. Eur J Med Chem 109:294–304

    Article  CAS  PubMed  Google Scholar 

  32. Schrödinger LLC, 2010 Glide, Version 5.6. New York, NY

  33. Sivan SK, Manga V (2010) Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J Mol Model 16:1169–1178

    Article  CAS  PubMed  Google Scholar 

  34. Sybyl-X-2.1 version, 2013. Tripos Inc., and Certara, St. Louis (MO)

  35. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228

    Article  CAS  Google Scholar 

  36. Chitta A, Sivan SK, Manga V (2014) 3D QSAR based design of novel oxindole derivative as 5HT7 inhibitors. J Recept Signal Transduct Res 34:185–194

    Article  CAS  PubMed  Google Scholar 

  37. Cramer RDIII, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA) 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967

    Article  CAS  PubMed  Google Scholar 

  38. Singh U, Gangwal RP, Dhoke GV, Prajapati R, Damre M, Sangamwar AT (2017) 3D-QSAR and molecular docking analysis of (4-piperidinyl)-piperazines as acetyl-CoA carboxylases inhibitors. Arab J Chem 10:S617–S626

    Article  CAS  Google Scholar 

  39. Pires DE, Blundell TL, Ascher DB (2015) pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 58:4066–4072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We greatly acknowledge Tripos Inc., USA, and Schrödinger LLC, New York, for providing the software. The author Saikiran Reddy Peddi (IF150172) would like to acknowledge the financial support from DST for a research fellowship.

Funding

This research was made possible through grants from DST-SERB (SB/EMEQ-004/2013) New Delhi, India.

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Authors and Affiliations

  1. Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, 500007, India

    Saikiran Reddy Peddi & Vijjulatha Manga

  2. College of Education for Pure Sciences Ibn al-Haytham, University of Baghdad, Baghdad, Iraq

    Nihaya Abdulsattear Mohammed & Ammar Adil Hussein

  3. Department of Chemistry, Nizam College, Osmania University, Hyderabad, 500001, India

    Sree Kanth Sivan

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  1. Saikiran Reddy Peddi
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  2. Nihaya Abdulsattear Mohammed
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  3. Ammar Adil Hussein
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  5. Vijjulatha Manga
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Correspondence to Vijjulatha Manga.

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Electronic supplementary material

Supplementary information consists of toxicity profile of dataset compounds calculated from pkCSM online server.

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Peddi, S.R., Mohammed, N.A., Hussein, A.A. et al. Multiple-receptor conformation docking, dock pose clustering, and 3D QSAR-driven approaches exploring new HIV-1 RT inhibitors. Struct Chem 29, 999–1012 (2018). https://doi.org/10.1007/s11224-018-1082-8

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  • DOI: https://doi.org/10.1007/s11224-018-1082-8

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