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Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype.

Beaulieu PL, Coulombe R, Duan J, Fazal G, Godbout C, Hucke O, Jakalian A, Joly MA, Lepage O, Llinàs-Brunet M, Naud J, Poirier M, Rioux N, Thavonekham B, Kukolj G, Stammers TA
Bioorg Med Chem Lett 23 4132-40 (2013)
Cited: 11 times
EuropePMC logo PMID: 23768906

Abstract

We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.

Reviews - 4jjs mentioned but not cited (1)

  1. RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. Venkataraman S, Prasad BVLS, Selvarajan R. Viruses 10 E76 (2018)


Reviews citing this publication (2)

  1. Pharmaceutical prospects of naturally occurring quinazolinone and its derivatives. He D, Wang M, Zhao S, Shu Y, Zeng H, Xiao C, Lu C, Liu Y. Fitoterapia 119 136-149 (2017)
  2. Structural biology in antiviral drug discovery. Bassetto M, Massarotti A, Coluccia A, Brancale A. Curr Opin Pharmacol 30 116-130 (2016)

Articles citing this publication (8)

  1. Discovery of Novel Hepatitis C Virus NS5B Polymerase Inhibitors by Combining Random Forest, Multiple e-Pharmacophore Modeling and Docking. Wei Y, Li J, Qing J, Huang M, Wu M, Gao F, Li D, Hong Z, Kong L, Huang W, Lin J. PLoS One 11 e0148181 (2016)
  2. Antiviral effect, safety, and pharmacokinetics of five-day oral administration of Deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C. Larrey D, Lohse AW, Trepo C, Bronowicki JP, Arastéh K, Bourlière M, Calleja JL, Stern JO, Nehmiz G, Abdallah N, Berger KL, Marquis M, Steffgen J, Kukolj G, BI 207127 Study Group. Antimicrob Agents Chemother 57 4727-4735 (2013)
  3. Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potency in the cell-based replicon assay. Stammers TA, Coulombe R, Duplessis M, Fazal G, Gagnon A, Garneau M, Goulet S, Jakalian A, LaPlante S, Rancourt J, Thavonekham B, Wernic D, Kukolj G, Beaulieu PL. Bioorg Med Chem Lett 23 6879-6885 (2013)
  4. Haptic-driven, interactive drug design: implementing a GPU-based approach to evaluate the induced fit effect. Anthopoulos A, Pasqualetto G, Grimstead I, Brancale A. Faraday Discuss 169 323-342 (2014)
  5. Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers. Kovács É, Ali H, Minorics R, Traj P, Resch V, Paragi G, Bruszel B, Zupkó I, Mernyák E. Molecules 28 1196 (2023)
  6. A study of the allosteric inhibition of HCV RNA-dependent RNA polymerase and implementing virtual screening for the selection of promising dual-site inhibitors with low resistance potential. Ismail NSM, Elzahabi HSA, Sabry P, Baselious FN, AbdelMalak AS, Hanna F. J Recept Signal Transduct Res 37 341-354 (2017)
  7. Combination of pharmacophore hypothesis and molecular docking to identify novel inhibitors of HCV NS5B polymerase. Harikishore A, Li E, Lee JJ, Cho NJ, Yoon HS. Mol Divers 19 529-539 (2015)
  8. Novel 6-Aminoquinazolinone Derivatives as Potential Cross GT1-4 HCV NS5B Inhibitors. Nasr T, Aboshanab AM, Mpekoulis G, Drakopoulos A, Vassilaki N, Zoidis G, Abouzid KAM, Zaghary W. Viruses 14 2767 (2022)


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