Dataset Information

Paromomycin: A potential dual targeted drug effectively inhibits both spike (S1) and main protease of COVID-19.

ABSTRACT:

Objectives

With the increasing number of people suffering from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a dire need to look for effective remedies against this pandemic. Drug repurposing seems to be the solution for the current situation.

Methods

In a quest to find a potential drug against this virus, 15 antimalarial drugs (including chloroquine) and 2413 US Food and Drug Administration-approved drugs were investigated for activity against both the protease and spike proteins of SARS-CoV-2 using an in silico approach. Molecular docking analysis followed by molecular dynamics simulation was performed to estimate the binding and stability of the complexes.

Results

This study identified a single drug - paromomycin - with activity against two targets of SARS-CoV-2, i.e., spike protein (S1) and protease domain. Paromomycin was found to have strong binding affinity for both targets of coronavirus. The results also showed that no antimalarial drug exhibited effective binding for either S1 or protease.

Conclusions

This study found that paromomycin may be an effective dual targeting drug against coronavirus, as it binds not only to the protease domain of the virion, but also to the spike domain, with high stability. Furthermore, none of the antimalarial drugs showed strong binding affinity for either protease or the receptor binding domain (RBD).

SUBMITTER: Tariq A

PROVIDER: S-EPMC7306207 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Paromomycin: A potential dual targeted drug effectively inhibits both spike (S1) and main protease of COVID-19.

Tariq Asma A Mateen Rana Muhammad RM Afzal Muhammad Sohail MS Saleem Mahjabeen M

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 20200621

<h4>Objectives</h4>With the increasing number of people suffering from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a dire need to look for effective remedies against this pandemic. Drug repurposing seems to be the solution for the current situation.<h4>Methods</h4>In a quest to find a potential drug against this virus, 15 antimalarial drugs (including chloroquine) and 2413 US Food and Drug Administration-approved drugs wer ...[more]

PMID: 32579907

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Project description:COVID-19 is currently considered the ninth-deadliest pandemic, spreading through direct or indirect contact with infected individuals. It has imposed a consistent strain on both the financial and healthcare resources of many countries. To address this challenge, there is a pressing need for the development of new potential therapeutic agents for the treatment of this disease. To identify potential antiviral agents as novel dual inhibitors of SARS-CoV-2, we retrieved 404 alkaloids from 12 selected medicinal antiviral plants and virtually screened them against the renowned catalytic sites and favorable interacting residues of two essential proteins of SARS-CoV-2, namely, the main protease and spike glycoprotein. Based on docking scores, 12 metabolites with dual inhibitory potential were subjected to drug-likeness, bioactivity scores, and drug-like ability analyses. These analyses included the ligand-receptor stability and interactions at the potential active sites of target proteins, which were analyzed and confirmed through molecular dynamic simulations of the three lead metabolites. We also conducted a detailed binding free energy analysis of pivotal SARS-CoV-2 protein inhibitors using molecular mechanics techniques to reveal their interaction dynamics and stability. Overall, our results demonstrated that 12 alkaloids, namely, adouetine Y, evodiamide C, ergosine, hayatinine, (+)-homoaromoline, isatithioetherin C, N,alpha-L-rhamnopyranosyl vincosamide, pelosine, reserpine, toddalidimerine, toddayanis, and zanthocadinanine, are shortlisted as metabolites based on their interactions with target proteins. All 12 lead metabolites exhibited a higher unbound fraction and therefore greater distribution compared with the standards. Particularly, adouetine Y demonstrated high docking scores but exhibited a nonspontaneous binding profile. In contrast, ergosine and evodiamide C showed favorable binding interactions and superior stability in molecular dynamics simulations. Ergosine demonstrated exceptional performance in several key pharmaceutical metrics. Pharmacokinetic evaluations revealed that ergosine exhibited pronounced bioactivity, good absorption, and optimal bioavailability. Additionally, it was predicted not to cause skin sensitivity and was found to be non-hepatotoxic. Importantly, ergosine and evodiamide C emerged as superior drug candidates for dual inhibition of SARS-CoV-2 due to their strong binding affinity and drug-like ability, comparable to known inhibitors like N3 and molnupiravir. This study is limited by its in silico nature and demands the need for future in vitro and in vivo studies to confirm these findings.

Dataset Information

Paromomycin: A potential dual targeted drug effectively inhibits both spike (S1) and main protease of COVID-19.

Objectives

Methods

Results

Conclusions

Publications

Paromomycin: A potential dual targeted drug effectively inhibits both spike (S1) and main protease of COVID-19.

Similar Datasets

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