Abstract:Monkeypox is a zoonotic disease caused by a DNA virus known as Monkeypox virus. Generally, Monkeypox disease is considered a self-limiting condition with symptoms similar to that of smallpox disease. Most cases of Monkeypox are considered mild but some patients may suffer from serious complications. Due to the high similarity between Monkeypox virus and smallpox virus, therefore vaccines and antiviral therapies originally intended for use against smallpox can be effective also in Monkeypox infection cases. How… Show more
“…It was found that dihydroergotamine showed efficient binding with the proteins and inhibited Mpox cysteine proteinase. These findings support further in-vitro and in-vivo studies on dehydroergotamine for potential therapy against Mpox [60].…”
BackgroundWhile the world is still facing the global pandemic COVID‐19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the pathogenesis, symptoms, and management strategies will aid in the development of potent therapeutics for the treatment of monkeypox virus infection.ObjectivesTo get insight into the current treatment and prevention strategies will aid in effectively coping with the disease.MethodsFor obtaining information regarding the ongoing treatment and prevention strategies and the drugs under pipeline, we referred to Google Scholar, Pub Med, Pub Chem, and WHO official site.ResultsThere are a few drugs that came out to be effective for the treatment of Mpox. Tecovirimat acts by inhibiting viral replication and viral wrapping. Another drug is cidofovir, which hinders the activity of viral DNA polymerase but has the drawback of nephrotoxicity. To overcome this, a conjugate of cidofovir is being used—known as brincidofovir—which has a similar mechanism as cidofovir but lesser toxicity. Ribavirin acts via inhibiting inosine monophosphate dehydrogenase (IMPDPH) thus disrupting viral translation. It also interferes with helicase activity. Tiazofurin, Adenosine N1 oxide, and HPMPA have shown efficacy in in‐vitro studies by inhibiting IMPDH, DNA polymerase, and viral mRNA translation respectively. In‐silico studies have proven the effect of nilotinib, simeprevir, and dihydroergotamine for Mpox treatment. They have shown binding affinity for proteins required for the growth and release of MPXV. Vaccines have also been employed for the prevention of Mpox, which includes JYNNEOS, ACAM2000, and VIGIV.ConclusionThis review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.
“…It was found that dihydroergotamine showed efficient binding with the proteins and inhibited Mpox cysteine proteinase. These findings support further in-vitro and in-vivo studies on dehydroergotamine for potential therapy against Mpox [60].…”
BackgroundWhile the world is still facing the global pandemic COVID‐19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the pathogenesis, symptoms, and management strategies will aid in the development of potent therapeutics for the treatment of monkeypox virus infection.ObjectivesTo get insight into the current treatment and prevention strategies will aid in effectively coping with the disease.MethodsFor obtaining information regarding the ongoing treatment and prevention strategies and the drugs under pipeline, we referred to Google Scholar, Pub Med, Pub Chem, and WHO official site.ResultsThere are a few drugs that came out to be effective for the treatment of Mpox. Tecovirimat acts by inhibiting viral replication and viral wrapping. Another drug is cidofovir, which hinders the activity of viral DNA polymerase but has the drawback of nephrotoxicity. To overcome this, a conjugate of cidofovir is being used—known as brincidofovir—which has a similar mechanism as cidofovir but lesser toxicity. Ribavirin acts via inhibiting inosine monophosphate dehydrogenase (IMPDPH) thus disrupting viral translation. It also interferes with helicase activity. Tiazofurin, Adenosine N1 oxide, and HPMPA have shown efficacy in in‐vitro studies by inhibiting IMPDH, DNA polymerase, and viral mRNA translation respectively. In‐silico studies have proven the effect of nilotinib, simeprevir, and dihydroergotamine for Mpox treatment. They have shown binding affinity for proteins required for the growth and release of MPXV. Vaccines have also been employed for the prevention of Mpox, which includes JYNNEOS, ACAM2000, and VIGIV.ConclusionThis review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.
“…Molecular dynamics simulation mainly focuses on calculating the natural dynamics of biomolecular structures on the different timescale in a solution. This also helps calculate each atom's fluid properties and movement in a system in a given set of times 43 . So, the selected protein–ligand complexes of both MPXV proteins were observed to understand the stability of the complex under 300 ns MD simulation.…”
Monkeypox viral infection is an emerging threat and a major concern for the human population. The lack of drug molecules to treat this disease may worsen the problem. Identifying potential drug targets can significantly improve the process of developing potent drug molecules for treating monkeypox. The proteins responsible for viral replication are attractive drug targets. Identifying potential inhibitors from known drug molecules that target these proteins can be key to finding a cure for monkeypox. In this work, two viral proteins, DNA-dependent RNA polymerase (DdRp) and viral core cysteine proteinase, were considered as potential drug targets. Sixteen antibiotic drugs from the tetracycline class were screened against both viral proteins through high-throughput virtual screening. These tetracycline class of antibiotic drugs have the ability to inhibit bacterial protein synthesis, which makes these antibiotics drugs a prominent candidate for drug repurposing. Based on the screening result obtained against DdRp, top two compounds, namely Tigecycline and Eravacycline with docking scores of − 8.88 and − 7.87 kcal/mol, respectively, were selected for further analysis. Omadacycline and minocycline, with docking scores of − 10.60 and − 7.51 kcal/mol, are the top two compounds obtained after screening proteinase with the drug library. These compounds, along with reference compounds GTP for DdRp and tecovirimat for proteinase, were used to form protein–ligand complexes, followed by their evaluation through a 300 ns molecular dynamic simulation. The MM/GBSA binding free energy calculation and principal components analysis of these selected complexes were also conducted for understanding the dynamic stability and binding affinity of these compounds with respective target proteins. Overall, this study demonstrates the repurposing of tetracycline-derived drugs as a therapeutic solution for monkeypox viral infection.
“…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). The drugs IDs, 2D structures, name and docking score are shown in Table 1.…”
Amid the ongoing monkeypox outbreak, there is an urgent need for the rapid development of effective therapeutic interventions capable of countering the immune evasion mechanisms employed by the monkeypox virus (MPXV). The evasion strategy involves the binding of the F3L protein to dsRNA, resulting in diminished interferon (IFN) production. Consequently, our current research focuses on utilizing virtual drug screening techniques to target the RNA binding domain of the F3L protein. Out of the 954 compounds within the South African natural compound database, only four demonstrated notable docking scores: −6.55, −6.47, −6.37, and −6.35 kcal/mol. The dissociation constant (KD) analysis revealed a stronger binding affinity of the top hits 1-4 (−5.34, −5.32, −5.29, and −5.36 kcal/mol) with the F3L in the MPXV. All-atom simulations of the top-ranked hits 1 to 4 consistently exhibited stable dynamics, suggesting their potential to interact effectively with interface residues. This was further substantiated through analyses of parameters such as radius of gyration (Rg), Root Mean Square Fluctuation, and hydrogen bonding. Cumulative assessments of binding free energy confirmed the top-performing candidates among all the compounds, with values of −35.90, −52.74, −28.17, and −32.11 kcal/mol for top hits 1-4, respectively. These results indicate that compounds top hit 1-4 could hold significant promise for advancing innovative drug therapies, suggesting their suitability for both in vivo and in vitro experiments.
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