Computational and Statistical Approach Reveals Lichen Metabolites as Potential Inhibitor for PLpro and Nsp12 RNA Polymerase Drug Targets of SARS-CoV-2

SARS-CoV-2 frequently mutates, producing variants that challenge current treatments. As therapeutic options remain limited, small molecules, particularly natural products, offer promising alternatives. This study screened a manually curated library of lichen-derived compounds targeting Papain-like protease (PLpro) (PDB ID: 6W9C) and RNA dependent RNA polymerase (RdRp) (Nsp12, PDB ID: 6M71) using computational and statistical methods. Targeted virtual screening and ADMET analysis identified four active compounds: compounds: fallacinal (ligand ID 892), haematommone (ligand ID 1102), alectorialic acid (ligand ID 3172), and barbatolic acid (ligand ID 4202). PLpro inhibitors interacted with residues ASN88, LYS92, ASN156, ARG82, ALA39, LYS43, and LYS82, while RdRp inhibitors bound to ARG555, LYS545, ARG836, ARG858, ALA550, LYS551, and ILE548. Principal component analysis revealed that ligands 1102, 3172, and 4202 occupy a chemical space closely aligned with known inhibitors. The BOILED-Egg plot indicated ligand 1102 has favorable pharmacokinetics, suggesting good intestinal absorption without blood-brain barrier penetration. Molecular dynamics simulations, including RMSD, RMSF, and MM-GBSA calculations, confirmed moderate stability of the ligand 1102-protein complex. These findings underscore the therapeutic potential of lichen-derived compounds as dual inhibitors of PLpro and RdRp, offering a promising direction for SARS-CoV-2 drug development.