Exploring the inhibitory potential of Lippia Javanica phytochemicals against SARS-CoV-2 Omicron variant Mpro using molecular modelling approaches

Amidst the emergence of SARS-CoV-2 variants and the persistence of long-term COVID-19 complications, the search for novel therapeutics remains a global priority. Lippia javanica, a Southern African herb traditionally used for respiratory conditions, gained prominence as a home remedy during the COVID-19 pandemic. This study represents the first in silico investigation into the inhibitory potential of 116 phytochemicals from L. javanica, identified through LC-MS and previous literature, against the SARS-CoV-2 Omicron variant main protease (Mpro), with nirmatrelvir serving as the reference inhibitor. Using a combination of molecular modelling approaches, physicochemical and toxicity profiling, and bioactivity prediction, five phytochemicals demonstrated competitive binding profiles relative to nirmatrelvir. Remarkably, isoverbascoside exhibited the strongest binding affinity (-9.2 kcal/mol), forming key hydrogen bonds, alkyl, π-alkyl, and van der Waals interactions. Despite a few candidates violating Lipinski’s Rule of Five due to high molecular weight, they displayed favourable lipophilicity, predicted bioactivity, and low toxicity. MD simulations further confirmed the structural stability of isoverbascoside, crassifolioside, and verbascoside within the Mpro binding pocket, with binding free energies of -58.16, -48.12, and − 46.54 kcal/mol, respectively, substantially surpassing that of nirmatrelvir (-34.68 kcal/mol). Stability analyses via RMSD, RMSF, and RoG metrics corroborated the dynamic integrity of these complexes. In all, the findings highlight the promising inhibitory potential of L. javanica phytochemicals, particularly isoverbascoside, against SARS-CoV-2 Mpro, warranting further experimental validation to confirm their therapeutic applicability.