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.

Omicron, a variant of concern (VOC) of SARS-CoV-2, emerged in South Africa in November 2021. Omicron has been continuously acquiring a series of new mutations, especially in the spike (S) protein that led to high infectivity and transmissibility. Peptides targeting the receptor-binding domain (RBD) of the spike protein by which omicron and its variants attach to the host receptor, angiotensin-converting enzyme (ACE2) can block the viral infection at the first step. This study aims to identify antiviral peptides from the Antiviral peptide database (AVPdb) and HIV-inhibitory peptide database (HIPdb) against the RBD of omicron by using a molecular docking approach. The lead RBD binder peptides obtained through molecular docking were screened for allergenicity and physicochemical criteria (isoelectric point (pI) and net charge) required for peptide-based drugs. The binding affinity of the best five peptide inhibitors with the RBD of omicron was validated further by molecular dynamics (MD) simulation. Our result introduces five antiviral peptides, including AVP1056, AVP1059, AVP1225, AVP1801, and HIP755, that may effectively hinder omicron-host interactions. It is worth mentioning that all the three major sub-variants of omicron, BA.1 (B.1.1.529.1), BA.2 (B.1.1.529.2), and BA.3 (B.1.1.529.3), exhibits conserved ACE-2 interacting residues. Hence, the screened antiviral peptides with similar affinity can also interrupt the RBD-mediated invasion of different major sub-variants of omicron. Altogether, these peptides can be considered in the peptide-based therapeutics development for omicron treatment after further experimentation. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-022-03258-4.

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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.

Monkeypox is a zoonotic disease caused by the Poxviridiea family virus Monkeypox. According to the Centers for Disease Control and Prevention, 70,420 monkeypox virus infections had been reported in 107 countries as of October 6, 2022. New studies have concluded that the monkeypox outbreak is caused by a strain with a unique mutation, increasing the possibility that the virus may develop resistance to current medicines by accumulating mutations in therapeutic targets. As peptide‐based therapeutics impede the drug target through multiple interactions, it may offer a better therapeutic solution to the possible drug resistance issue related to monkeypox treatment. Therefore, in this work, we screened an antiviral peptide library, the CPP site 2.0 database, against the p37 target protein using molecular docking approaches. The p37 is required for the viral pathogen's successful egression and spread. The allergenicity and physicochemical properties of the peptides were thoroughly analyzed before the molecular docking studies for selecting druggable candidates. The interactions of the peptides bearing the highest docking score were validated further by using molecular dynamics (MD) simulation studies. Our investigation revealed that two cell‐penetrating peptides of the CPP site 2.0 database might effectively prevent the egression and spread of the MPXV by inhibiting p37. Following more testing, these peptides can be explored in developing peptide‐based therapies against the MPX therapy.

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