2. Academic Validation
  3. Synthesis, biological evaluation and in silico modeling of novel pan-genotypic NS5A inhibitors

Synthesis, biological evaluation and in silico modeling of novel pan-genotypic NS5A inhibitors

  • Bioorg Med Chem. 2020 Oct 15;28(20):115716. doi: 10.1016/j.bmc.2020.115716.
Andrey A Ivashchenko 1,  Yan A Ivanenkov 2,  Vladimir A Aladinskiy 3,  Ruben N Karapetian 4,  Angela G Koryakova 4,  Alexey A Ryakhovskiy 4,  Oleg D Mitkin 4,  Dmitry V Kravchenko 4,  Nikolai P Savchuk 5,  Bogdan A Zagribelnyy 3,  Alexander V Ivashchenko 6
Affiliations

Affiliations

  • 1 Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia; ChemDiv, 6605 Nancy Ridge Drive San Diego, CA 92121, United States; Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russia.
  • 2 ChemDiv, 6605 Nancy Ridge Drive San Diego, CA 92121, United States; Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia. Electronic address: [email protected].
  • 3 Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny City, Moscow Region 141700, Russia.
  • 4 Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia.
  • 5 Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia; Avisa Pharmaceuticals LLC, 1835 E. Hallandale Beach Blvd, #442, Hallandale Beach, Fl 33009, United States.
  • 6 Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia; ChemDiv, 6605 Nancy Ridge Drive San Diego, CA 92121, United States; Avisa Pharmaceuticals LLC, 1835 E. Hallandale Beach Blvd, #442, Hallandale Beach, Fl 33009, United States.
PMID: 33069072 DOI: 10.1016/j.bmc.2020.115716
Abstract

A series of novel small-molecule pan-genotypic hepatitis C virus (HCV) NS5A inhibitors with picomolar activity containing 2-[(2S)-pyrrolidin-2-yl]-5-[4-(4-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}buta-1,3-diyn-1-yl)phenyl]-1H-imidazole core was designed based on molecular modeling study and SAR analysis. The constructed in silico model and docking study provide a deep insight into the binding mode of this type of NS5A inhibitors. Based on the predicted binding interface we have prioritized the most crucial diversity points responsible for improving Antiviral activity. The synthesized molecules were tested in a cell-based assay, and compound 1.12 showed an EC50 value in the range of 2.9-34 pM against six genotypes of NS5A HCV, including gT3a, and demonstrated favorable pharmacokinetic profile in rats. This lead compound can be considered as an attractive candidate for further clinical evaluation.

Keywords

Combinatorial synthesis; HCV; In silico modeling; Medicinal chemistry; NS5A inhibitors.

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