Advanced virtual screening enables the discovery of a host-targeting and broad-spectrum antiviral agent.
Garri Chilingaryan, Roza Izmailyan, Rafayela Grigoryan, Anastasiya Shavina, Erik Arabyan, Hamlet Khachatryan, Narek Abelyan, Mher Matevosyan, Vardan Harutyunyan, Gayane Manukyan, Benjamin Hietel, Anna Shtro, Daria Danilenko, Hovakim Zakaryan
Author Information
Garri Chilingaryan: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia; Biocentric.AI, 0051, Yerevan, Armenia.
Roza Izmailyan: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia.
Rafayela Grigoryan: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia.
Anastasiya Shavina: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia; Denovo Sciences Inc., Yerevan, Armenia.
Erik Arabyan: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia.
Hamlet Khachatryan: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia; Denovo Sciences Inc., Yerevan, Armenia.
Narek Abelyan: Biocentric.AI, 0051, Yerevan, Armenia; Institute of Biomedicine and Pharmacy, Russian-Armenian University, 0051, Yerevan, Armenia.
Gayane Manukyan: Laboratory of Molecular and Cellular Immunology, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia.
Benjamin Hietel: Fraunhofer Institute for Cell Therapy and Immunology IZI Department of Drug Design and Target Validation MWT Biocenter, Weinbergweg 22, 06120, Halle (Saale), Germany.
Anna Shtro: Smorodintsev Research Institute of Influenza, 197376, St. Petersburg, Russia.
Daria Danilenko: Smorodintsev Research Institute of Influenza, 197376, St. Petersburg, Russia.
Hovakim Zakaryan: Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, 0014, Yerevan, Armenia; Denovo Sciences Inc., Yerevan, Armenia. Electronic address: h_zakaryan@mb.sci.am.
We employed an advanced virtual screening (AVS) approach to identify potential inhibitors of human dihydroorotate dehydrogenase (DHODH), a validated target for development of broad-spectrum antivirals. We screened a library of 495118 compounds and identified 495 compounds that exhibited better binding scores than the reference ligands involved in the screening. From the top 100 compounds, we selected 28 based on their consensus docking scores and structural novelty. Then, we conducted in vitro experiments to investigate the antiviral activity of selected compounds on HSV-1 infection, which is susceptible to DHODH inhibitors. Among the tested compounds, seven displayed statistically significant antiviral effects, with Comp 19 being the most potent inhibitor. We found that Comp 19 exerted its antiviral effect in a dose-dependent manner (IC = 1.1 μM) and exhibited the most significant antiviral effect when added before viral infection. In the biochemical assay, Comp 19 inhibited human DHODH in a dose-dependent manner with the IC value of 7.3 μM. Long-timescale molecular dynamics simulations (1000 ns) revealed that Comp 19 formed a very stable complex with human DHODH. Comp 19 also displayed broad-spectrum antiviral activity and suppressed cytokine production in THP-1 cells. Overall, our study provides evidence that AVS could be successfully implemented to discover novel DHODH inhibitors with broad-spectrum antiviral activity.
