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Identifying potential human and medicinal plant microRNAs against SARS-CoV-2 3'UTR region: A computational genomics assessment.

ABSTRACT: The coronavirus disease of 2019 (COVID-19) began as an outbreak and has taken a toll on human lives. The current pandemic requires scientific attention; hence we designed a systematic computational workflow to identify the cellular microRNAs (miRNAs) from human host possessing the capability to target and silence 3'UTR of SARS-CoV-2 genome. Based on this viewpoint, we extended our miRNA search to medicinal plants like Ocimum tenuiflorum, Zingiber officinale and Piper nigrum, which are well-known to possess antiviral properties, and are often consumed raw or as herbal decoctions. Such an approach, that makes use of miRNA of one species to interact and silence genes of another species including viruses is broadly categorized as cross-kingdom interactions. As a part of our genomics study on host-virus-plant interaction, we identified one unique 3'UTR conserved site 'GGAAGAG' amongst 5024 globally submitted SARS-CoV-2 complete genomes, which can be targeted by the human miRNA 'hsa-miR-1236-3p' and by Z. officinale miRNA 'zof-miR2673b'. Additionally, we also predicted that the members of miR477 family commonly found in these three plant genomes possess an inherent potential to silence viral genome RNA and facilitate antiviral defense against SARS-CoV-2 infection. In conclusion, this study reveals a universal site in the SARS-CoV-2 genome that may be crucial for targeted therapeutics to cure COVID-19.

SUBMITTER: Mangukia N

PROVIDER: S-EPMC8288231 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Identifying potential human and medicinal plant microRNAs against SARS-CoV-2 3'UTR region: A computational genomics assessment.

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