In-Silico characterisation of antiviral activities of marine fungal derivatives: Focusing on TMPRSS2 as a therapeutic target

Marine fungi represent an underexplored source of bioactive metabolites with significant antiviral potential. The enzyme TMPRSS2, which primes the SARS-CoV-2 spike protein, is a crucial target for preventing viral entry into cells. Natural TMPRSS2 inhibitors derived from marine fungi offer promising therapeutic possibilities. The study evaluated the TMPRSS2-inhibiting potential of 10 antiviral marine fungal derivatives using molecular docking with the Schrödinger Glide software against the co-crystal structure of TMPRSS2 (PDB ID: 7Y0F). Drug-likeness was assessed after docking using QikProp. Molecular dynamics simulations were performed over 120 ns using Desmond, analysing stability parameters such as RMSD, RMSF, solvent-accessible surface area, binding free energy, and radius of gyration. The compounds Norlichexanthone (-6.618 kcal/mol) and Alterporriol Q (-6.516 kcal/mol) demonstrated strong binding to the TMPRSS2 catalytic residues. Norlichexanthone formed stable hydrogen bonds with Ser436, Ser441, and Ser460, while Alterporriol Q engaged through hydrogen bonds and a salt bridge involving His296, Ser441, Ser436, and Lys342. MD simulations indicated stable binding and structural stability, with Norlichexanthone showing advantageous compactness and a binding energy of -120.72 kcal/mol. Alterporriol Q stabilised after initial fluctuations and maintained a significant binding energy of -127.66 kcal/mol. Predictions of drug-likeness favoured Norlichexanthone for oral bioavailability, whereas Alterporriol Q’s high molecular weight and lower absorption suggested the need for optimisation. Norlichexanthone and Alterporriol Q could serve as promising natural scaffolds for TMPRSS2 inhibition and broad-spectrum antiviral development, with Norlichexanthone being especially notable for its drug-like properties.