Advanced virtual screening enables the discovery of a host-targeting and broad-spectrum antiviral agent

• Published in: Antiviral research 2023-09, Vol.217, p.105681-105681, Article 105681
• Main Authors: Chilingaryan, Garri, Izmailyan, Roza, Grigoryan, Rafayela, Shavina, Anastasiya, Arabyan, Erik, Khachatryan, Hamlet, Abelyan, Narek, Matevosyan, Mher, Harutyunyan, Vardan, Manukyan, Gayane, Hietel, Benjamin, Shtro, Anna, Danilenko, Daria, Zakaryan, Hovakim
• Format: Article
• Language: English
• Subjects: Antiviral; DHODH; HSV-1; Pyrimidine; Screening
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2023.105681

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 (IC50 = 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 IC50 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. •Advanced virtual screening was performed to discover inhibitors against DHODH.•7 out of 28 identified compounds demonstrated antiviral activity against HSV-1.•Antiviral activity of compounds was reversed by the addition of uridine.•Comp 19, the most potent compound, displayed broad-spectrum antiviral activity.•Comp 19 inhibited the production of cytokines.