Identification of FDA-approved drugs with triple targeting mode of action for the treatment of monkeypox: a high throughput virtual screening study

Abstract

According to the Center for Disease Control and Prevention, as of August 23, 94 countries had confirmed 42,954 Monkeypox Virus cases. As specific monkeypox drugs are not yet developed, the treatment depends on repurposed FDA-approved drugs. According to a recent study, the Monkeypox outbreak is caused by a strain with a unique mutation, raising the likelihood that the virus will develop resistance to current drugs by acquiring mutations in the targets of currently used drugs. The probability of multiple mutations in two or more drug targets at a time is always low than mutation in a single drug target. Therefore, we identified 15 triple-targeting FDA-approved drugs that can inhibit three viral targets, including topoisomerase1, p37, and thymidylate kinase, using high throughput virtual screening approach. Further, the molecular dynamics simulation analysis of the top hits such as Naldemedine and Saquinavir with their respective targets reveals the formation of stable conformational changes of the ligand–protein complexes inside the dynamic biological environment. We suggest further research on these triple-targeting molecules to develop an effective therapy for the currently spreading Monkeypox. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-023-10636-4.

Exploring the natural products chemical space to abrogate the F3L-dsRNA interface of monkeypox virus to enhance the immune responses using molecular screening and free energy calculations

“…Based on the high docking score only four compounds, namely, (3R,5S)-3-[(3S,5S,9R,10S,13S,14R,16R,17R)-16-hydroxy-10,13-dimethyl-3-[(2R,3S,4S,5R,6S)-3,4,5-trihyd, [(2S, 3S,6E,10E,14E,18R)-2,3,18,19-tetrahydroxy-2,6,11,15,19-pentamethyl-icosa-6,10,14-trienyl], 8-oxo-16-[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxy-hexadecanoic, (2R)-2-[(3S, 4S)-3,4-dihydroxy-2,2-dimethyl-8-(4-methylpent-3 -enoxy)chroman-6- yl]-5,7-dihydroxy-chrom with a docking score of −6.55 kcal/mol, −6.47 kcal/mol, −6.37 kcal/mol and −6.35 kcal/mol respectively. A similar approach has been used by the previous study which uses the FDA approved drugs against the three different targets such as topoisomerase1, p37, and thymidylate kinase of the monkey pox virus ( Srivastava et al, 2023 ). Another study used drug screening against monkey pox virus cysteine proteinase ( Odhar, 2022 ).…”

“…A similar approach has been used by the previous study which uses the FDA approved drugs against the three different targets such as topoisomerase1, p37, and thymidylate kinase of the monkey pox virus (Srivastava et al, 2023). Another study used drug screening against monkey pox virus cysteine proteinase (Odhar, 2022).…”

An in‐silico‐based study identified peptide inhibitors that can block the egression of the monkeypox virus by inhibiting the p37 protein target

“…The nucleotide stretch identified in the monkeypox genome has 99.19% similarity with the p37 gene of the vaccinia virus. [ 25 ] The protein sequence (372 amino acids) of MPV p37 was obtained through the translation of gene sequence using the Expasy server (https://web.expasy.org/translate/). In the protein–protein blast study, the protein sequence has shown 99.9% identity with p37 of the Vaccinia virus.…”

“…[ 26 ] The interacting amino acid residues of Monkeypox's p37 protein were identified by sequence alignment with p37 of the vaccinia virus. [ 25 ] The p37 modeled structure was validated by evaluating the conformational orientation, QMEAN score, and global model quality estimation (GMQE) through the structure assessment tool and Ramachandran plot. GMQE scores range from 0 to 1, with higher scores indicating more reliable models.…”

Exploring monkeypox virus proteins and rapid detection techniques

“…Li et al (2022a) found that the F13 sequence is highly conserved in MPXV and VARV, and similarity ranges from 97.58% to 99.73%. Similarly, Srivastava et al (2023) conducted a protein-protein blast analysis, revealing a sequence alignment similarity of 99.9% between MPXV and VACV. As a result, tecovirimat, formerly approved for treating smallpox, has shown potential for treating mpox.…”