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Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors
Elissa A Fink; Conner Bardine; Stefan Gahbauer; Isha Singh; Kris White; Shuo Gu; Xiaobo Wan; Beatrice Ary; Isabelle Glenn; Pavla Fajtova; Jiankun Lyu; Seth Vigneron; Nicholas J Young; Ivan S Kondratov; Yurii Moroz; Jack Taunton; Adam R Renslo; John J Irwin; Adolfo Garcia-Sastre; Brian K Shoichet; Charles S Craik.
Afiliación
  • Elissa A Fink; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Conner Bardine; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Stefan Gahbauer; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Isha Singh; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Kris White; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Shuo Gu; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Xiaobo Wan; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Beatrice Ary; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Isabelle Glenn; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Pavla Fajtova; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, San Diego, CA, USA
  • Jiankun Lyu; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Seth Vigneron; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Nicholas J Young; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Ivan S Kondratov; Enamine Ltd. Kyiv, Ukraine
  • Yurii Moroz; Chemspace LLC, Kyiv, Ukraine
  • Jack Taunton; Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA, USA
  • Adam R Renslo; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • John J Irwin; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Adolfo Garcia-Sastre; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • Brian K Shoichet; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
  • Charles S Craik; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
Preprint en Inglés | bioRxiv | ID: ppbiorxiv-498881
ABSTRACT
Antiviral therapeutics to treat SARS-CoV-2 are much desired for the on-going pandemic. A well-precedented viral enzyme is the main protease (MPro), which is now targeted by an approved drug and by several investigational drugs. With the inevitable liabilities of these new drugs, and facing viral resistance, there remains a call for new chemical scaffolds against MPro. We virtually docked 1.2 billion non-covalent and a new library of 6.5 million electrophilic molecules against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 M and 20 M, respectively. Several series were optimized, resulting in inhibitors active in the low micromolar range. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. Together, these compounds reveal new chemotypes to aid in further discovery of MPro inhibitors for SARS-CoV-2 and other future coronaviruses.
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Texto completo: Disponible Colección: Preprints Base de datos: bioRxiv Tipo de estudio: Estudio pronóstico Idioma: Inglés Año: 2022 Tipo del documento: Preprint
Texto completo
Añadir a Mi BVS
Imprimir
XML
Buscar en Google
Texto completo: Disponible Colección: Preprints Base de datos: bioRxiv Tipo de estudio: Estudio pronóstico Idioma: Inglés Año: 2022 Tipo del documento: Preprint