A sudden onset of an emergent viral pathogen, SARS-CoV-2, manifested globally in late December 2019, originating in Wuhan, China, swiftly precipitating the COVID-19 pandemic. Subsequent to its rapid dissemination, intensive research efforts have been dedicated to identifying effective therapeutic modalities to counteract this formidable virus. In this context, a computational scrutiny of compounds derived from Artocarpus altilis (breadfruit) was undertaken to discern potential inhibitors of the SARS-CoV-2 main protease (Mpro) enzyme, crucial for viral replication. Initiating our investigation, a comprehensive drug-likeness analysis was employed to discern compounds with optimal pharmacological attributes. Subsequently, molecular docking studies were conducted, focusing on the Mpro enzyme, with selected compounds from A. altilis. Nirmatrelvir, an FDA-approved drug in combination with ritonavir, served as the benchmark inhibitor in these analyses. The compounds under investigation, namely cycloartomunin, dihydrocycloartomunin, cycloartobiloxanthone, artomunoxanthentrione, and cycloartomunoxanthone, demonstrated notable binding affinities of −7.6, −7.7, −7.7, −8.3, and −8.1 kcal/mol, respectively, in the molecular docking studies. Comparative analysis revealed nirmatrelvir to exhibit an affinity of −8.1 kcal/mol in the same docking environment. Subsequently, a comprehensive pharmacological assessment was undertaken, juxtaposing the top five test compounds with the standard inhibitor. Concomitant with this, a computational toxicity analysis was integral to our assessment. Ultimately, the investigated compounds displayed promising docking outputs coupled with moderate pharmacological profiles. This study advocates further experimental validations to ascertain the inhibitory potential of these A. altilis-derived compounds against the SARS-CoV-2 Mpro enzyme.
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