Synthesis, biological evaluation and in silico modeling of novel pangenotypic NS5A inhibitors
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 a...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2020-10, Vol.28 (20), Article 115716 |
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| creator | Ivashchenko, Andrey A. Ivanenkov, Yan A. Aladinskiy, Vladimir A. Karapetian, Ruben N. Koryakova, Angela G. Ryakhovskiy, Alexey A. Mitkin, Oleg D. Kravchenko, Dmitry Savchuk, Nikolai P. Zagribelnyy, Bogdan A. Ivashchenko, Alexander |
| description | 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. |
| doi_str_mv | 10.1016/j.bmc.2020.115716 |
| format | Article |
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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. 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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. 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| subjects | Biochemistry & Molecular Biology Chemistry Chemistry, Medicinal Chemistry, Organic Life Sciences & Biomedicine Pharmacology & Pharmacy Physical Sciences Science & Technology |
| title | Synthesis, biological evaluation and in silico modeling of novel pangenotypic NS5A inhibitors |
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