Medicinal Chemistry Research

, Volume 24, Issue 5, pp 1869–1883 | Cite as

Structure-based virtual screening and docking studies for the identification of novel inhibitors against wild and drug resistance strains of HIV-1 RT

  • Subhash Chander
  • Ashok Penta
  • Sankaranarayanan MurugesanEmail author
Original Research


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.


Virtual screening Docking Maybridge HIV Reverse transcriptase Mutation 



Authors gratefully acknowledge BITS-Pilani for providing the necessary facilities to do this work. This work was carried out under a Grant from Science and Engineering Research Board of Department of Science and Technology, New Delhi (Ref. No: SR/FT/LS-58/2011).

Conflict of interest

The authors declared that there is no conflict of interest.


  1. Asahchop EL, Wainberg MA, Oliveira M, Xu H, Brenner BG, Moisi D, Ibanescu IR, Tremblay C (2013) Distinct resistance patterns to etravirine and rilpivirine in viruses containing non-nucleoside reverse transcriptase inhibitor mutations at baseline. AIDS 27:879–887CrossRefPubMedGoogle Scholar
  2. Ballana E, Este JA (2013) Insights from host genomics into HIV infection and disease: identification of host targets for drug development. Antivir Res 100:473–486CrossRefPubMedGoogle Scholar
  3. Bell FW, Cantrell AS, Hoegberg M, Jaskunas SR, Johansson NG, Jordan CL, Kinnick MD, Lind P, Morin JM (1995) Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. Synthesis and basic structure activity relationship studies of PETT analogs. J Med Chem 38:4929–4936CrossRefPubMedGoogle Scholar
  4. Brechtl JR, Breitbart W, Galietta M, Krivo S, Rosenfeld B (2001) The use of highly active anti retroviral therapy (HAART) in patients with advanced HIV infection: impact on medical, palliative care and quality of life outcomes. J Pain Symptom Manag 21:41–51CrossRefGoogle Scholar
  5. Bustanji Y, Al-Masri IM, Qasem A, Al-Bakri AG, Taha MO (2009) In silico screening for non-nucleoside HIV-1 reverse transcriptase inhibitors using physiccochemical filters and highthroughput docking followed by in vitro evaluation. Chem Biol Drug Des 74:258–265CrossRefPubMedGoogle Scholar
  6. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW, Tang Y (2012) admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 52:3099–3105CrossRefPubMedGoogle Scholar
  7. Chong P, Sebahar P, Youngman M (2012) Rational design of potent non-nucleoside Inhibitors of HIV-1 reverse transcriptase. J Med Chem 55:10601–10609CrossRefPubMedGoogle Scholar
  8. Das K, Bauman JD, Clark AD (2008) High-resolution structures of HIV-1 reverse transcriptase TMC278 complexes: strategic flexibility explains potency against resistant mutations. Proc Natl Acad Sci USA 105:1466–1471CrossRefPubMedCentralPubMedGoogle Scholar
  9. Delaugerre C, Rohban R, Simon A (2001) Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen. J Med Virol 65:445–448CrossRefPubMedGoogle Scholar
  10. Emamzadeh-Fard S, Esmaeeli S, Arefi K, Moradbeigi M, Heidari B, Fard SE, Paydary K, Seyedalinaghi S (2013) Mechanisms of anti-retroviral drug resistance: implications for novel drug discovery and development. Infect Disord Drug Targets 13:330–336CrossRefPubMedGoogle Scholar
  11. Freitas RF, Galembeck SE (2006) Computational study of the interaction between TIBO inhibitors and Y181 (C181), K101 and Y188 amino acids. J Phys Chem 110:21287–21298CrossRefGoogle Scholar
  12. Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY, Ross C, Miyasaka T, Walker RT, Tanaka H, Stammers DK, Stuart DI (1996) Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J Med Chem 39:1589–1600CrossRefPubMedGoogle Scholar
  13. Hopkins AL, Ren J, Milton J, Hazen RJ, Chan JH, Stuart DI, Stammers DK (2004) Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. J Med Chem 47:5912–5922CrossRefPubMedGoogle Scholar
  14. Ivetac A, Swift SE, Boyer PL, Diaz A, Naughton J, Young AT, Hughes SH, McCammon JA (2014) Discovery of novel inhibitors of HIV-1 reverse transcriptase virtual screening of experimental and theoretical ensembles. Chem Biol Drug Des 83:521–531CrossRefPubMedCentralPubMedGoogle Scholar
  15. Jorgensen WL, Maxwell DS, Tirado RJ (1996) Development and testing of the OPLS all-atom force field on conformational energetics of organic liquids. J Am Chem Soc 118:11225–11236CrossRefGoogle Scholar
  16. Kozal MJ (2009) Drug-resistant human immunodeficiency virus. Clin Microbiol Infect 15:69–73CrossRefPubMedGoogle Scholar
  17. La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Este JA, Novellino E, Silvestri R (2012) New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors. J Med Chem 55:6634–6638CrossRefPubMedGoogle Scholar
  18. Murgueitio MS, Bermudez M, Mortier J, Wolber G (2012) In silico virtual screening approaches for anti-viral drug discovery. Drug Discov Today Technol 9:219–225CrossRefGoogle Scholar
  19. Nichols SE, Domaoal RA, Thakur VV, Tirado-Rives J, Anderson KS, Jorgensen WL (2009) Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures. J Chem Inf Model 49:1272–1279CrossRefPubMedCentralPubMedGoogle Scholar
  20. Paul AJ, Janssen PJ, Lewi PJ, Arnold E, Daeyaert F, Jonge M, Heeres J, Koymans L, Stoffels P (2005) In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 48:1901–1909CrossRefGoogle Scholar
  21. Penta A, Chander S, Ganguly S, Murugesan S (2014) De novo design and in silico studies of novel 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid derivatives as HIV-1 reverse transcriptase inhibitors. Med Chem Res 23:3662–3670CrossRefGoogle Scholar
  22. Ren J, Nichols CE, Chamberlain PP (2007) Relationship of potency and resilience to drug resistance mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu and Tyr188Cys mutant HIV-1 reverse transcriptases. J Med Chem 50:2301–2309CrossRefPubMedGoogle Scholar
  23. Reynolds C, Koning CB, Pelly SC, Otterlo WA, Bode ML (2012) In search of a treatment for HIV current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Chem Soc Rev 41:4657–4670CrossRefPubMedGoogle Scholar
  24. Romines KR, Freeman GA, Schaller LT, Cowan JR, Gonzales SS, Tidwell JH, Andrews CW 3rd, Stammers DK, Hazen RJ, Ferris RG, Short SA, Chan JH, Boone LR (2006) Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor. J Med Chem 49:727–739CrossRefPubMedGoogle Scholar
  25. Sarafianos SG, Das K, Hughes SH, Arnold E (2004) Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. Curr Opin Struct Biol 14:716–730CrossRefPubMedGoogle Scholar
  26. Sun LQ, Zhu L, Qian K (2012) Design, synthesis and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates. J Med Chem 55:7219–7229CrossRefPubMedCentralPubMedGoogle Scholar
  27. Yang S, Pannecouque C, Daelemans D, Xiao-Dong Ma, Liu Y, Fen-Er Chen, Clercq ED (2013) Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem 65:134–143CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Subhash Chander
    • 1
  • Ashok Penta
    • 1
  • Sankaranarayanan Murugesan
    • 1
    Email author
  1. 1.Medicinal Chemistry Research Laboratory, Department of PharmacyBirla Institute of Technology & SciencePilaniIndia

Personalised recommendations