Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus

Abstract

Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand–enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.

Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus

“…Using the rigid receptor docking protocol and GBVI/WSA scoring function, molecular docking ( Taha et al., 2023 ) of all FDA-approved drugs was performed. AutoDock Vina software was used to carry out the docking operation ( Ali et al., 2023 ) of the lowest docking score hits obtained from the MOE software to validate the docking protocol of the MOE software. Adding polar hydrogen atoms and assigning partial charges to each atom were all done using the AutoDock software, and the structure of ligands and receptors were saved in PDBQT format.…”

Identification of fungus-growing termite-associated halogenated-PKS maduralactomycin a as a potential inhibitor of MurF protein of multidrug-resistant Acinetobacter baumannii

“…Since new therapeutic development is challenging, time-consuming, and costly. Bioinformatics studies have been phenomenal in genome-wide studies (GWAS) to identify mutations (Khattak et al, 2021;Ahmad et al, 2022a), its annotation (Ahmad et al, 2022b;Shah et al, 2022) and impact (Ijaz et al, 2021;Ali et al, 2022a), identification of novel and potent drugs (Ajmal et al, 2022;Ali et al, 2023;Rehman et al, 2023), its targets (Jan et al, 2021) FIGURE 7 The interaction patterns and the fraction of MurF protein in complex with (A) Termstrin B and (B) Fridamycin A through the simulation period. The Histogram plot shows the fraction interaction of each residue, and the colour codes show the type of interaction, i.e., the green colour represents hydrogen bonds, the grey colour represents hydrophobic interactions, the purple colour represents ionic interactions, and the blue colour represents the water bridges.…”

The Neglected Mpox Virus: From Historical Review to Future Perspectives

“…Tecovirimat inhibits the spread of the virus within the infected host by inhibiting F13/VP37 [71]. Some studies have now demonstrated the potential of drugs targeting inhibition of the MPXV-F13 protein for the successful treatment of MPXV, although additional in vitro and in vivo experiments are still necessary [72,73]. Cidofovir is a broad-spectrum antiviral drug effective against almost all DNA viruses, and its anti-MPXV activity in vivo has been demonstrated in different monkey infection models [74].…”