1jla › Citations

Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors.

Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammers DK
J Mol Biol 312 795-805 (2001)
Related entries: 1c0t, 1c0u, 1c1b, 1c1c, 1dtq, 1dtt, 1ep4, 1jkh, 1jlb, 1jlc, 1jle, 1jlf, 1jlg, 1jlq, 1klm, 1rt1, 1rt2, 1rt3, 1rt4, 1rt5, 1rt6, 1rt7

Cited: 121 times
EuropePMC logo PMID: 11575933

Abstract

Mutations at either Tyr181 or Tyr188 within HIV-1 reverse transcriptase (RT) give high level resistance to many first generation non-nucleoside inhibitors (NNRTIs) such as the anti-AIDS drug nevirapine. By comparison second generation inhibitors, for instance the drug efavirenz, show much greater resilience to these mutations. In order to understand the structural basis for these differences we have determined a series of seven crystal structures of mutant RTs in complexes with first and second generation NNRTIs as well as one example of an unliganded mutant RT. These are Tyr181Cys RT (TNK-651) to 2.4 A, Tyr181Cys RT (efavirenz) to 2.6 A, Tyr181Cys RT (nevirapine) to 3.0 A, Tyr181Cys RT (PETT-2) to 3.0 A, Tyr188Cys RT (nevirapine) to 2.6 A, Tyr188Cys RT (UC-781) to 2.6 A and Tyr188Cys RT (unliganded) to 2.8 A resolution. In the two previously published structures of HIV-1 reverse transcriptase with mutations at 181 or 188 no side-chain electron density was observed within the p66 subunit (which contains the inhibitor binding pocket) for the mutated residues. In contrast the mutated side-chains can be seen in the NNRTI pocket for all seven structures reported here, eliminating the possibility that disordering contributes to the mechanism of resistance. In the case of the second generation compounds efavirenz with Tyr181Cys RT and UC-781 with Tyr188Cys RT there are only small rearrangements of either inhibitor within the binding site compared to wild-type RT and also for the first generation compounds TNK-651, PETT-2 and nevirapine with Tyr181Cys RT. For nevirapine with the Tyr188Cys RT there is however a more substantial movement of the drug molecule. We conclude that protein conformational changes and rearrangements of drug molecules within the mutated sites are not general features of these particular inhibitor/mutant combinations. The main contribution to drug resistance for Tyr181Cys and Tyr188Cys RT mutations is the loss of aromatic ring stacking interactions for first generation compounds, providing a simple explanation for the resilience of second generation NNRTIs, as such interactions make much less significant contribution to their binding.

Reviews - 1jla mentioned but not cited (1)

  1. Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review. Tarasova O, Poroikov V, Veselovsky A. Molecules 23 E1233 (2018)

Articles - 1jla mentioned but not cited (14)

  1. Variability in docking success rates due to dataset preparation. Corbeil CR, Williams CI, Labute P. J Comput Aided Mol Des 26 775-786 (2012)
  2. Automated docking screens: a feasibility study. Irwin JJ, Shoichet BK, Mysinger MM, Huang N, Colizzi F, Wassam P, Cao Y. J Med Chem 52 5712-5720 (2009)
  3. Frog2: Efficient 3D conformation ensemble generator for small compounds. Miteva MA, Guyon F, Tufféry P. Nucleic Acids Res 38 W622-7 (2010)
  4. Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents. Bollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL. J Med Chem 54 8582-8591 (2011)
  5. BSP-SLIM: a blind low-resolution ligand-protein docking approach using predicted protein structures. Lee HS, Zhang Y. Proteins 80 93-110 (2012)
  6. Conformational landscape of the human immunodeficiency virus type 1 reverse transcriptase non-nucleoside inhibitor binding pocket: lessons for inhibitor design from a cluster analysis of many crystal structures. Paris KA, Haq O, Felts AK, Das K, Arnold E, Levy RM. J Med Chem 52 6413-6420 (2009)
  7. Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile. Wang X, Zhang J, Huang Y, Wang R, Zhang L, Qiao K, Li L, Liu C, Ouyang Y, Xu W, Zhang Z, Zhang L, Shao Y, Jiang S, Ma L, Liu J. J Med Chem 55 2242-2250 (2012)
  8. Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures. Nichols SE, Domaoal RA, Thakur VV, Tirado-Rives J, Anderson KS, Jorgensen WL. J Chem Inf Model 49 1272-1279 (2009)
  9. Mining protein dynamics from sets of crystal structures using "consensus structures". van Westen GJ, Wegner JK, Bender A, Ijzerman AP, van Vlijmen HW. Protein Sci 19 742-752 (2010)
  10. What do docking and QSAR tell us about the design of HIV-1 reverse transcriptase nonnucleoside inhibitors? Paneth A, Płonka W, Paneth P. J Mol Model 23 317 (2017)
  11. Assessment of Nonnucleoside Inhibitors Binding to HIV-1 Reverse Transcriptase Using HYDE Scoring. Paneth A, Płonka W, Paneth P. Pharmaceuticals (Basel) 12 E64 (2019)
  12. High-throughput quantum-mechanics/molecular-mechanics (ONIOM) macromolecular crystallographic refinement with PHENIX/DivCon: the impact of mixed Hamiltonian methods on ligand and protein structure. Borbulevych O, Martin RI, Westerhoff LM. Acta Crystallogr D Struct Biol 74 1063-1077 (2018)
  13. A multilayer dynamic perturbation analysis method for predicting ligand-protein interactions. Gu L, Li B, Ming D. BMC Bioinformatics 23 456 (2022)
  14. HTLV-1 reverse transcriptase homology model provides structural basis for sensitivity to existing nucleoside/nucleotide reverse transcriptase inhibitors. Tardiota N, Jaberolansar N, Lackenby JA, Chappell KJ, O'Donnell JS. Virol J 21 14 (2024)


Reviews citing this publication (22)

  1. Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. Sarafianos SG, Marchand B, Das K, Himmel DM, Parniak MA, Hughes SH, Arnold E. J Mol Biol 385 693-713 (2009)
  2. The structural biology of HIV-1: mechanistic and therapeutic insights. Engelman A, Cherepanov P. Nat Rev Microbiol 10 279-290 (2012)
  3. Molecular basis of human immunodeficiency virus drug resistance: an update. Menéndez-Arias L. Antiviral Res 85 210-231 (2010)
  4. Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Ren J, Stammers DK. Virus Res 134 157-170 (2008)
  5. Conformational changes in HIV-1 reverse transcriptase induced by nonnucleoside reverse transcriptase inhibitor binding. Sluis-Cremer N, Temiz NA, Bahar I. Curr HIV Res 2 323-332 (2004)
  6. Targeting HIV: antiretroviral therapy and development of drug resistance. Menéndez-Arias L. Trends Pharmacol Sci 23 381-388 (2002)
  7. Retroviral reverse transcriptases. Herschhorn A, Hizi A. Cell Mol Life Sci 67 2717-2747 (2010)
  8. Clinical management of HIV-1 resistance. Paredes R, Clotet B. Antiviral Res 85 245-265 (2010)
  9. Clinical utility of current NNRTIs and perspectives of new agents in this class under development. Zhang Z, Hamatake R, Hong Z. Antivir Chem Chemother 15 121-134 (2004)
  10. Reverse transcription of the HIV-1 pandemic. Basavapathruni A, Anderson KS. FASEB J 21 3795-3808 (2007)
  11. Avoiding Drug Resistance in HIV Reverse Transcriptase. Cilento ME, Kirby KA, Sarafianos SG. Chem Rev 121 3271-3296 (2021)
  12. Drug resistance in non-B subtype HIV-1: impact of HIV-1 reverse transcriptase inhibitors. Singh K, Flores JA, Kirby KA, Neogi U, Sonnerborg A, Hachiya A, Das K, Arnold E, McArthur C, Parniak M, Sarafianos SG. Viruses 6 3535-3562 (2014)
  13. Reverse Transcription of Retroviruses and LTR Retrotransposons. Hughes SH. Microbiol Spectr 3 MDNA3-0027-2014 (2015)
  14. A reverse transcriptase-dependent mechanism plays central roles in fundamental biological processes. Spadafora C. Syst Biol Reprod Med 54 11-21 (2008)
  15. Emerging reverse transcriptase inhibitors for HIV-1 infection. Rai MA, Pannek S, Fichtenbaum CJ. Expert Opin Emerg Drugs 23 149-157 (2018)
  16. Inhibition of HIV-1 reverse transcription: basic principles of drug action and resistance. Götte M. Expert Rev Anti Infect Ther 2 707-716 (2004)
  17. A Structural View on Medicinal Chemistry Strategies against Drug Resistance. Agnello S, Brand M, Chellat MF, Gazzola S, Riedl R. Angew Chem Int Ed Engl 58 3300-3345 (2019)
  18. Clinical significance of HIV reverse-transcriptase inhibitor-resistance mutations. Ibe S, Sugiura W. Future Microbiol 6 295-315 (2011)
  19. Efavirenz for HIV-1 infection in adults: an overview. Fortin C, Joly V. Expert Rev Anti Infect Ther 2 671-684 (2004)
  20. Winning the arms race by improving drug discovery against mutating targets. Anderson AC. ACS Chem Biol 7 278-288 (2012)
  21. Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors. Santos LH, Ferreira RS, Caffarena ER. Mem Inst Oswaldo Cruz 110 847-864 (2015)
  22. Structure-enhanced methods in the development of non-nucleoside inhibitors targeting HIV reverse transcriptase variants. Frey KM. Future Microbiol 10 1767-1772 (2015)

Articles citing this publication (84)

  1. HIV drug resistance. Clavel F, Hance AJ. N Engl J Med 350 1023-1035 (2004)
  2. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R, Mattei E, Serafino A, Cassano A, Sinibaldi-Vallebona P, Garaci E, Barone C, Spadafora C. Oncogene 24 3923-3931 (2005)
  3. Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK. Proc Natl Acad Sci U S A 99 14410-14415 (2002)
  4. Allosteric inhibition through core disruption. Horn JR, Shoichet BK. J Mol Biol 336 1283-1291 (2004)
  5. Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase. Singh K, Marchand B, Kirby KA, Michailidis E, Sarafianos SG. Viruses 2 606-638 (2010)
  6. Characterization and structural analysis of novel mutations in human immunodeficiency virus type 1 reverse transcriptase involved in the regulation of resistance to nonnucleoside inhibitors. Ceccherini-Silberstein F, Svicher V, Sing T, Artese A, Santoro MM, Forbici F, Bertoli A, Alcaro S, Palamara G, d'Arminio Monforte A, Balzarini J, Antinori A, Lengauer T, Perno CF. J Virol 81 11507-11519 (2007)
  7. Aromatic-Aromatic Interactions Database, A(2)ID: an analysis of aromatic π-networks in proteins. Chourasia M, Sastry GM, Sastry GN. Int J Biol Macromol 48 540-552 (2011)
  8. Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors. Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Stammers DK. J Mol Biol 336 569-578 (2004)
  9. The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic. Namasivayam V, Vanangamudi M, Kramer VG, Kurup S, Zhan P, Liu X, Kongsted J, Byrareddy SN. J Med Chem 62 4851-4883 (2019)
  10. Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors. Pata JD, Stirtan WG, Goldstein SW, Steitz TA. Proc Natl Acad Sci U S A 101 10548-10553 (2004)
  11. Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT. Shen L, Shen J, Luo X, Cheng F, Xu Y, Chen K, Arnold E, Ding J, Jiang H. Biophys J 84 3547-3563 (2003)
  12. Distinct mutation pathways of non-subtype B HIV-1 during in vitro resistance selection with nonnucleoside reverse transcriptase inhibitors. Lai MT, Lu M, Felock PJ, Hrin RC, Wang YJ, Yan Y, Munshi S, McGaughey GB, Tynebor RM, Tucker TJ, Williams TM, Grobler JA, Hazuda DJ, McKenna PM, Miller MD. Antimicrob Agents Chemother 54 4812-4824 (2010)
  13. Increased expression and copy number amplification of LINE-1 and SINE B1 retrotransposable elements in murine mammary carcinoma progression. Gualtieri A, Andreola F, Sciamanna I, Sinibaldi-Vallebona P, Serafino A, Spadafora C. Oncotarget 4 1882-1893 (2013)
  14. Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138. Ren J, Nichols CE, Stamp A, Chamberlain PP, Ferris R, Weaver KL, Short SA, Stammers DK. FEBS J 273 3850-3860 (2006)
  15. The N348I mutation at the connection subdomain of HIV-1 reverse transcriptase decreases binding to nevirapine. Schuckmann MM, Marchand B, Hachiya A, Kodama EN, Kirby KA, Singh K, Sarafianos SG. J Biol Chem 285 38700-38709 (2010)
  16. The "Connection" Between HIV Drug Resistance and RNase H. Delviks-Frankenberry KA, Nikolenko GN, Pathak VK. Viruses 2 1476-1503 (2010)
  17. Reverse transcriptase inhibitors induce cell differentiation and enhance the immunogenic phenotype in human renal clear-cell carcinoma. Landriscina M, Altamura SA, Roca L, Gigante M, Piscazzi A, Cavalcanti E, Costantino E, Barone C, Cignarelli M, Gesualdo L, Ranieri E. Int J Cancer 122 2842-2850 (2008)
  18. Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants. Frey KM, Puleo DE, Spasov KA, Bollini M, Jorgensen WL, Anderson KS. J Med Chem 58 2737-2745 (2015)
  19. Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. Liang X, Lee CJ, Zhao J, Toone EJ, Zhou P. J Med Chem 56 6954-6966 (2013)
  20. Characterization of a subtype D human immunodeficiency virus type 1 isolate that was obtained from an untreated individual and that is highly resistant to nonnucleoside reverse transcriptase inhibitors. Gao Y, Paxinos E, Galovich J, Troyer R, Baird H, Abreha M, Kityo C, Mugyenyi P, Petropoulos C, Arts EJ. J Virol 78 5390-5401 (2004)
  21. Cross-clade inhibition of recombinant human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus SIVcpz reverse transcriptases by RNA pseudoknot aptamers. Held DM, Kissel JD, Thacker SJ, Michalowski D, Saran D, Ji J, Hardy RW, Rossi JJ, Burke DH. J Virol 81 5375-5384 (2007)
  22. Altered viral fitness and drug susceptibility in HIV-1 carrying mutations that confer resistance to nonnucleoside reverse transcriptase and integrase strand transfer inhibitors. Hu Z, Kuritzkes DR. J Virol 88 9268-9276 (2014)
  23. N348I in HIV-1 reverse transcriptase can counteract the nevirapine-mediated bias toward RNase H cleavage during plus-strand initiation. Biondi MJ, Beilhartz GL, McCormick S, Götte M. J Biol Chem 285 26966-26975 (2010)
  24. High-throughput structure-based pharmacophore modelling as a basis for successful parallel virtual screening. Steindl TM, Schuster D, Wolber G, Laggner C, Langer T. J Comput Aided Mol Des 20 703-715 (2006)
  25. Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors. Yang Y, Kang D, Nguyen LA, Smithline ZB, Pannecouque C, Zhan P, Liu X, Steitz TA. Elife 7 e36340 (2018)
  26. HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate. Maga G, Radi M, Gerard MA, Botta M, Ennifar E. Viruses 2 880-899 (2010)
  27. Quantum computational analysis for drug resistance of HIV-1 reverse transcriptase to nevirapine through point mutations. He X, Mei Y, Xiang Y, Zhang DW, Zhang JZ. Proteins 61 423-432 (2005)
  28. Nevirapine induces growth arrest and premature senescence in human cervical carcinoma cells. Stefanidis K, Loutradis D, Vassiliou LV, Anastasiadou V, Kiapekou E, Nikas V, Patris G, Vlachos G, Rodolakis A, Antsaklis A. Gynecol Oncol 111 344-349 (2008)
  29. Prediction of HIV drug resistance from genotype with encoded three-dimensional protein structure. Yu X, Weber IT, Harrison RW. BMC Genomics 15 Suppl 5 S1 (2014)
  30. 5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family. Mai A, Artico M, Ragno R, Sbardella G, Massa S, Musiu C, Mura M, Marturana F, Cadeddu A, Maga G, La Colla P. Bioorg Med Chem 13 2065-2077 (2005)
  31. Binding energy analysis for wild-type and Y181C mutant HIV-1 RT/8-Cl TIBO complex structures: quantum chemical calculations based on the ONIOM method. Saen-oon S, Kuno M, Hannongbua S. Proteins 61 859-869 (2005)
  32. Homodimerization of the p51 subunit of HIV-1 reverse transcriptase. Zheng X, Mueller GA, Cuneo MJ, Derose EF, London RE. Biochemistry 49 2821-2833 (2010)
  33. Retrotransposon-encoded reverse transcriptase in the genesis, progression and cellular plasticity of human cancer. Sinibaldi-Vallebona P, Matteucci C, Spadafora C. Cancers (Basel) 3 1141-1157 (2011)
  34. Solution characterization of [methyl-(13)C]methionine HIV-1 reverse transcriptase by NMR spectroscopy. Zheng X, Mueller GA, DeRose EF, London RE. Antiviral Res 84 205-214 (2009)
  35. Quantum study of mutational effect in binding of efavirenz to HIV-1 RT. Mei Y, He X, Xiang Y, Zhang DW, Zhang JZ. Proteins 59 489-495 (2005)
  36. Treatment response and drug resistance in patients infected with HIV type 1 group O viruses. Rodes B, de Mendoza C, Rodgers M, Newell A, Jimenez V, Lopez-Brugada RM, Soriano V. AIDS Res Hum Retroviruses 21 602-607 (2005)
  37. Bridge water mediates nevirapine binding to wild type and Y181C HIV-1 reverse transcriptase--evidence from molecular dynamics simulations and MM-PBSA calculations. Treesuwan W, Hannongbua S. J Mol Graph Model 27 921-929 (2009)
  38. Reinduction of cell differentiation and 131I uptake in a poorly differentiated thyroid tumor in response to the reverse transcriptase (RT) inhibitor nevirapine. Modoni S, Landriscina M, Fabiano A, Fersini A, Urbano N, Ambrosi A, Cignarelli M. Cancer Biother Radiopharm 22 289-295 (2007)
  39. Structures, functions and adaptations of the human LINE-1 ORF2 protein. Baldwin ET, van Eeuwen T, Hoyos D, Zalevsky A, Tchesnokov EP, Sánchez R, Miller BD, Di Stefano LH, Ruiz FX, Hancock M, Işik E, Mendez-Dorantes C, Walpole T, Nichols C, Wan P, Riento K, Halls-Kass R, Augustin M, Lammens A, Jestel A, Upla P, Xibinaku K, Congreve S, Hennink M, Rogala KB, Schneider AM, Fairman JE, Christensen SM, Desrosiers B, Bisacchi GS, Saunders OL, Hafeez N, Miao W, Kapeller R, Zaller DM, Sali A, Weichenrieder O, Burns KH, Götte M, Rout MP, Arnold E, Greenbaum BD, Romero DL, LaCava J, Taylor MS. Nature 626 194-206 (2024)
  40. Design, synthesis, and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with an improved drug resistance profile. Jiang HX, Zhuang DM, Huang Y, Cao XX, Yao JH, Li JY, Wang JY, Zhang C, Jiang B. Org Biomol Chem 12 3446-3458 (2014)
  41. Docking analysis and resistance evaluation of clinically relevant mutations associated with the HIV-1 non-nucleoside reverse transcriptase inhibitors nevirapine, efavirenz and etravirine. Alcaro S, Alteri C, Artese A, Ceccherini-Silberstein F, Costa G, Ortuso F, Bertoli A, Forbici F, Santoro MM, Parrotta L, Flandre P, Masquelier B, Descamps D, Calvez V, Marcelin AG, Perno CF, Sing T, Svicher V. ChemMedChem 6 2203-2213 (2011)
  42. Modelling the binding of HIV-reverse transcriptase and nevirapine: an assessment of quantum mechanical and force field approaches and predictions of the effect of mutations on binding. Raju RK, Burton NA, Hillier IH. Phys Chem Chem Phys 12 7117-7125 (2010)
  43. Novel 1,3-dihydro-benzimidazol-2-ones and their analogues as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Monforte AM, Logoteta P, De Luca L, Iraci N, Ferro S, Maga G, De Clercq E, Pannecouque C, Chimirri A. Bioorg Med Chem 18 1702-1710 (2010)
  44. The interplay of structure and dynamics: insights from a survey of HIV-1 reverse transcriptase crystal structures. Seckler JM, Leioatts N, Miao H, Grossfield A. Proteins 81 1792-1801 (2013)
  45. The phenylmethylthiazolylthiourea nonnucleoside reverse transcriptase (RT) inhibitor MSK-076 selects for a resistance mutation in the active site of human immunodeficiency virus type 2 RT. Auwerx J, Stevens M, Van Rompay AR, Bird LE, Ren J, De Clercq E, Oberg B, Stammers DK, Karlsson A, Balzarini J. J Virol 78 7427-7437 (2004)
  46. Cell differentiation and iodine-131 uptake in poorly differentiated thyroid tumour in response to nevirapine. Landriscina M, Modoni S, Fabiano A, Fersini A, Barone C, Ambrosi A, Cignarelli M. Lancet Oncol 7 877-879 (2006)
  47. In vitro evaluation of the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. Dong JJ, Zhou Y, Liu YT, Zhang ZW, Zhou XJ, Wang HJ, Liao L. Mol Cell Endocrinol 370 113-118 (2013)
  48. Sequence and structure based models of HIV-1 protease and reverse transcriptase drug resistance. Masso M, Vaisman II. BMC Genomics 14 Suppl 4 S3 (2013)
  49. Anti-human immunodeficiency virus type 1 activity of novel 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives. Ordonez P, Hamasaki T, Isono Y, Sakakibara N, Ikejiri M, Maruyama T, Baba M. Antimicrob Agents Chemother 56 2581-2589 (2012)
  50. Effect of translocation defective reverse transcriptase inhibitors on the activity of N348I, a connection subdomain drug resistant HIV-1 reverse transcriptase mutant. Michailidis E, Singh K, Ryan EM, Hachiya A, Ong YT, Kirby KA, Marchand B, Kodama EN, Mitsuya H, Parniak MA, Sarafianos SG. Cell Mol Biol (Noisy-le-grand) 58 187-195 (2012)
  51. Mechanistic Study of Common Non-Nucleoside Reverse Transcriptase Inhibitor-Resistant Mutations with K103N and Y181C Substitutions. Lai MT, Munshi V, Lu M, Feng M, Hrin-Solt R, McKenna PM, Hazuda DJ, Miller MD. Viruses 8 E263 (2016)
  52. Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues. Zhang Z, Zheng M, Du L, Shen J, Luo X, Zhu W, Jiang H. J Comput Aided Mol Des 20 281-293 (2006)
  53. Indolyl aryl sulphones as HIV-1 non-nucleoside reverse transcriptase inhibitors: synthesis, biological evaluation and binding mode studies of new derivatives at indole-2-carboxamide. De Martino G, La Regina G, Ragno R, Coluccia A, Bergamini A, Ciaprini C, Sinistro A, Maga G, Crespan E, Artico M, Silvestri R. Antivir Chem Chemother 17 59-77 (2006)
  54. Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics. Debnath U, Verma S, Jain S, Katti SB, Prabhakar YS. J Comput Aided Mol Des 27 637-654 (2013)
  55. Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors. Sbardella G, Mai A, Bartolini S, Castellano S, Cirilli R, Rotili D, Milite C, Santoriello M, Orlando S, Sciamanna I, Serafino A, Lavia P, Spadafora C. J Med Chem 54 5927-5936 (2011)
  56. Synthesis and biological evaluation of 6-substituted 5-alkyl-2-(phenylaminocarbonylmethylthio)pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs. Yu M, Li Z, Liu S, Fan E, Pannecouque C, De Clercq E, Liu X. ChemMedChem 6 826-833 (2011)
  57. A study of the binding energies of efavirenz to wild-type and K103N/Y181C HIV-1 reverse transcriptase based on the ONIOM method. Srivab P, Hannongbua S. ChemMedChem 3 803-811 (2008)
  58. Revealing the drug-resistant mechanism for diarylpyrimidine analogue inhibitors of HIV-1 reverse transcriptase. Zhang H, Qin F, Ye W, Li Z, Ma S, Xia Y, Jiang Y, Zhu J, Li Y, Zhang J, Chen HF. Chem Biol Drug Des 78 427-437 (2011)
  59. Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study. Ashford MW, Xu C, Molloy JJ, Carpenter-Warren C, Slawin AMZ, Leach AG, Watson AJB, Watson AJB. Chemistry 26 12249-12255 (2020)
  60. Flexible docking of pyridinone derivatives into the non-nucleoside inhibitor binding site of HIV-1 reverse transcriptase. Medina-Franco JL, Rodríguez-Morales S, Juárez-Gordiano C, Hernández-Campos A, Jiménez-Barbero J, Castillo R. Bioorg Med Chem 12 6085-6095 (2004)
  61. Inhibition activities of catechol diether based non-nucleoside inhibitors against the HIV reverse transcriptase variants: Insights from molecular docking and ONIOM calculations. Samanta PN, Das KK. J Mol Graph Model 75 294-305 (2017)
  62. Inhibitory activity of 9-phenylcyclohepta[d]pyrimidinedione derivatives against different strains of HIV-1 as non-nucleoside reverse transcriptase inhibitors. Huang Y, Wang X, Yu X, Yuan L, Guo Y, Xu W, Liu T, Liu J, Shao Y, Ma L. Virol J 8 230 (2011)
  63. Structural Insights to Human Immunodeficiency Virus (HIV-1) Targets and Their Inhibition. Vanangamudi M, Nair PC, Engels SEM, Palaniappan S, Namasivayam V. Adv Exp Med Biol 1322 63-95 (2021)
  64. Discovery, synthesis, and optimization of an N-alkoxy indolylacetamide against HIV-1 carrying NNRTI-resistant mutations from the Isatis indigotica root. Xu C, Xin Y, Chen M, Ba M, Guo Q, Zhu C, Guo Y, Shi J. Eur J Med Chem 189 112071 (2020)
  65. Drug resistant mechanism of diaryltriazine analog inhibitors of HIV-1 reverse transcriptase using molecular dynamics simulation and 3D-QSAR. Li Z, Zhang H, Li Y, Zhang J, Chen HF. Chem Biol Drug Des 77 63-74 (2011)
  66. Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors. Wright DW, Hall BA, Kellam P, Coveney PV. Biology (Basel) 1 222-244 (2012)
  67. HIV-1 Reverse Transcriptase Inhibition by Major Compounds in a Kenyan Multi-Herbal Composition (CareVid™): In Vitro and In Silico Contrast. Rotich W, Sadgrove NJ, Mas-Claret E, Padilla-González GF, Guantai A, Langat MK. Pharmaceuticals (Basel) 14 1009 (2021)
  68. Impact of Y181C and/or H221Y mutation patterns of HIV-1 reverse transcriptase on phenotypic resistance to available non-nucleoside and nucleoside inhibitors in China. Guo W, Li H, Zhuang D, Jiao L, Liu S, Li L, Liu Y, Gui T, Jia L, Li J. BMC Infect Dis 14 237 (2014)
  69. Indolyl aryl sulphones as HIV-1 reverse transcriptase inhibitors: docking and 3D QSAR studies. Ragno R, Coluccia A, La Regina G, Silvestri R. Expert Opin Drug Discov 2 87-114 (2007)
  70. 1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus. Geisman AN, Valuev-Elliston VT, Ozerov AA, Khandazhinskaya AL, Chizhov AO, Kochetkov SN, Pannecouque C, Naesens L, Seley-Radtke KL, Novikov MS. Bioorg Med Chem 24 2476-2485 (2016)
  71. Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors. Schauer G, Leuba S, Sluis-Cremer N. Biomolecules 3 889-904 (2013)
  72. Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study. Zhou Z, Meng B, An J, Zhao F, Sun Y, Zeng D, Wang W, Gao S, Xia Y, Dun C, De Clercq E, Pannecouque C, Zhan P, Kang D, Liu X. Int J Mol Sci 24 1215 (2023)
  73. Design of nevirapine derivatives insensitive to the K103N and Y181C HIV-1 reverse transcriptase mutants. Saparpakorn P, Hannongbua S, Rognan D. SAR QSAR Environ Res 17 183-194 (2006)
  74. Emergence of an NNRTI resistance mutation Y181C in an HIV-infected NNRTI-naive patient. Magiorkinis E, Paraskevis D, Sambatakou H, Gargalianos P, Haida C, Vassilakis A, Hatzakis A. AIDS Res Hum Retroviruses 24 413-415 (2008)
  75. In silico structure-based design of a potent, mutation resilient, small peptide inhibitor of HIV-1 reverse transcriptase. Rao GS, Bhatnagar S. J Biomol Struct Dyn 21 171-178 (2003)
  76. Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure. Biswas A, Choudhuri I, Arnold E, Lyumkis D, Haldane A, Levy RM. Proc Natl Acad Sci U S A 121 e2316662121 (2024)
  77. Multiple drugs and multiple targets: an analysis of the electrostatic determinants of binding between non-nucleoside HIV-1 reverse transcriptase inhibitors and variants of HIV-1 RT. Minkara MS, Davis PH, Radhakrishnan ML. Proteins 80 573-590 (2012)
  78. Small Conformational Changes Underlie Evolution of Resistance to NNRTI in HIV Reverse Transcriptase. Srivastava A, Birari V, Sinha S. Biophys J 118 2489-2501 (2020)
  79. Synthesis and Anti-HIV-1 Activity of a Novel Series of Aminoimidazole Analogs. Ganguly S, Murugesan S, Prasanthi N, Alptürk O, Herman B, Sluis-Cremer N. Lett Drug Des Discov 7 318-323 (2010)
  80. Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase. Barnard JP, Huber KD, Sluis-Cremer N. Antimicrob Agents Chemother 63 e00676-19 (2019)
  81. Identification of 3-((1-(Benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrazine-2-carboxylic Acid as a Potential Inhibitor of Non-Nucleosidase Reverse Transcriptase Inhibitors through InSilico Ligand- and Structure-Based Approaches. Mathpal D, Almeleebia TM, Alshahrani KM, Alshahrani MY, Ahmad I, Asiri M, Kamal M, Jawaid T, Srivastava SP, Saeed M, Balaramnavar VM. Molecules 26 5262 (2021)
  82. Identification of Adjacent NNRTI Binding Pocket in Multi-mutated HIV1- RT Enzyme Model: An in silico Study. Kamil RF, Debnath U, Verma S, Prabhakar YS. Curr HIV Res 16 121-129 (2018)
  83. Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase. Wang Y, Wang A, Wang J, Wu X, Sun Y, Wu Y. Molecules 27 7348 (2022)
  84. Molecular docking based design of Inhibitors for viral Non-Nucleosidase as potential anti-retroviral agents. Alharbi A, Alshaghdali K, Saeed A. Bioinformation 16 736-741 (2020)


Related citations provided by authors (15)

  1. 2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.. Chan JH, Hong JS, Hunter RN, Orr GF, Cowan JR, Sherman DB, Sparks SM, Reitter BE, Andrews CW, Hazen RJ, St Clair M, Boone LR, Ferris RG, Creech KL, Roberts GB, Short SA, Weaver K, Ott RJ, Ren J, Hopkins A, Stuart DI, Stammers DK J Med Chem 44 1866-82 (2001)
  2. Structural Basis for the Resilience of Efavirenz (Dmp-266) to Drug Resistant Mutations in HIV-1 Reverse Transcriptase. Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK Structure 8 1089-1094 (2000)
  3. Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding.. Ren J, Nichols C, Bird LE, Fujiwara T, Sugimoto H, Stuart DI, Stammers DK J Biol Chem 275 14316-20 (2000)
  4. Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses.. Ren J, Diprose J, Warren J, Esnouf RM, Bird LE, Ikemizu S, Slater M, Milton J, Balzarini J, Stuart DI, Stammers DK J Biol Chem 275 5633-9 (2000)
  5. Crystallographic analysis of the binding modes of thiazoloisoindolinone non-nucleoside inhibitors to HIV-1 reverse transcriptase and comparison with modeling studies.. Ren J, Esnouf RM, Hopkins AL, Stuart DI, Stammers DK J Med Chem 42 3845-51 (1999)
  6. Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants.. Hopkins AL, Ren J, Tanaka H, Baba M, Okamato M, Stuart DI, Stammers DK J Med Chem 42 4500-5 (1999)
  7. Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives.. Ren J, Esnouf RM, Hopkins AL, Warren J, Balzarini J, Stuart DI, Stammers DK Biochemistry 37 14394-403 (1998)
  8. 3'-Azido-3'-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes.. Ren J, Esnouf RM, Hopkins AL, Jones EY, Kirby I, Keeling J, Ross CK, Larder BA, Stuart DI, Stammers DK Proc Natl Acad Sci U S A 95 9518-23 (1998)
  9. Continuous and discontinuous changes in the unit cell of HIV-1 reverse transcriptase crystals on dehydration.. Esnouf RM, Ren J, Garman EF, Somers DO, Ross CK, Jones EY, Stammers DK, Stuart DI Acta Crystallogr D Biol Crystallogr 54 938-53 (1998)
  10. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor.. Esnouf RM, Ren J, Hopkins AL, Ross CK, Jones EY, Stammers DK, Stuart DI Proc Natl Acad Sci U S A 94 3984-9 (1997)
  11. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors.. Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY, Ross C, Miyasaka T, Walker RT, Tanaka H, Stammers DK, Stuart DI J Med Chem 39 1589-600 (1996)
  12. The Structure of HIV-1 Reverse Transcriptase Complexed with 9-Chloro-TIBO: Lessons for Inhibitor Design. Ren J, Esnouf RM, Hopkins AL, Ross CK, Jones EY, Stammers DK, Stuart DI Structure 3 915-926 (1995)
  13. High Resolution Structures of HIV-1 RT from Four RT-Inhibitor Complexes. Ren J, Esnouf RM, Garman E, Somers DO, Ross CK, Kirby I, Keeling J, Darby G, Jones EY, Stuart DI, Stammers DK Nat. Struct. Biol. 2 293-302 (1995)
  14. Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Non-Nucleoside Inhibitors. Esnouf RM, Ren J, Ross CK, Jones EY, Stammers DK, Stuart DI Nat. Struct. Biol. 2 303-308 (1995)
  15. Crystals of HIV-1 reverse transcriptase diffracting to 2.2 A resolution.. Stammers DK, Somers DO, Ross CK, Kirby I, Ray PH, Wilson JE, Norman M, Ren JS, Esnouf RM, Garman EF J Mol Biol 242 586-8 (1994)

Quick links