In Silico Identification of Phytochemical Inhibitors Targeting Human Metapneumo Virus: A Multi platform Docking Study with Molecular level Studies

BACKGROUND-The devastating impacts of COVID-19 have created a critical need for all researchers worldwide to be equipped with drugs against the potential HMPV F-protein (PDB: 8VT3). As chemical compounds are known to cause resistance, the quest for natural, plant-based analogues has gained more popularity among researchers. METHODS-Based on ethnopharmacological properties, four phytochemicals: cadinol (cloves), cineole (cardamom), curcumin (turmeric) and epicatechin (cinnamon), were selected. In the next step, the four phytochemicals were treated as ligands and Molecular docking was performed against HMPV pre-fusion F-protein, treated as receptor with PDB ID:8VT3 and chains G and I. The tools employed for docking include: PyRX (Autodoc Vina), MZ(SMINA) and SWISS DOCK (Autodoc Vina). Each of the tools generated 9 binding poses per ligand. The binding stability was then validated by performing Molecular dynamics (MD) simulations using iMODS (normal mode). Pharmacophore modelling was then performed, specifying interaction mechanisms such as hydrogen bonding, van der Waals contacts, charge analyses, salt-bridge analyses, solvation analyses, π-π interactions, and π-cations’ interactions. The four phytochemicals were subjected to ADMET profiling using Swiss ADME. Cross-platform analyses were performed based on Mean ± SD. RESULTS: Strong binding affinities were evidenced for the three ligands: cadinol -7.8 kcal/mol (MZ), -3.1 kcal/mol (Swiss Dock), -6.2 ±0.3 kcal/mol (PyRX) ; cineole -6.5±0.2 kcal/mol (PyRX), -6.3±0.3 kcal/mol (MZ), and -2.7±0.3 kcal/mol (Swiss Dock); curcumin -6.0 ±0.8 kcal/mol (PyRX), -5.8 ±0.5 kcal/mol (MZ) and -5.9 ±0.8 kcal/mol (Swiss Dock). On the other hand, epicatechin revealed weak binding affinities:-2.4 ±0.3 kcal/mol (PyRX) -2.0±0.2kcal/mol (MZ) and -1.0±0.2 kcal/mol (Swiss dock). These binding affinities are comparable to synthetic HMPV inhibitors like GS-441524(-8.2 kcal/mol approx.), EIDD-1931(-7.5kcal/mol approx) and PC-786(-7.8 kcal/mol approx). Structural stability of the receptor was confirmed by a low eigenvalue: 1.946 x 10-5. Pharmacophore interactions revealed H-bonds and Vander Waals contacts within 3Å, for the lead compounds and interestingly, curcumin revealed charge complementarity. Cross-platform validation through consistent rankings for curcumin and epicatechin were found. ADMET analyses confirmed their drug-likeliness without any kind of violations. CONCLUSION: The lead compounds: cadinol, cineole and curcumin are computationally predicted for HMPV F-protein inhibition and Consequently require wet lab analyses like cell-based assays, cytotoxic assessments, qRT-PCR and plaque assays. Consequently, this predictive study mitigates the problem of antiviral resistance associated with synthetic antiviral compounds, as phytochemicals are used as antiviral compounds against HMPV F-protein inhibitors.