MERGED LIGAND-BASED AND STRUCTURE-BASED VIRTUAL SCREENING FOR THE SELECTION OF NATURAL COMPOUNDS AS POTENTIAL INHIBITORS FOR THE CORE DOMAIN OF THE M2-1 PROTEIN OF HUMAN RESPIRATORY SYNCYTIAL VIRUS

The human Respiratory Syncytial Virus (hRSV) infection is the most common cause of severe lower track respiratory diseases in young children, older adults, and immunocompromised patients worldwide. The United Nations has produced a guide entitled "Preventing the Next Pandemic", which highlights hRSV as one of the viruses that require vigilance. In the viral replication cycle, the interaction between the M2-1 anti-termination factor and phosphoprotein P is important for the success of viral transcription. The M2-1 protein plays a crucial role in preventing the RNA-dependent RNA polymerase replication complex from disassociating upon reaching the codon stop, increasing transcriptional efficiency. The M2-1/P interaction occurs between the core domain of M2-1 (cdM2-1) and the intrinsically disordered region (IDR) of residues 90–110 of P (P90-110). In the present study, a merged ligand-based and structure-based virtual screening of 406,747 unique natural compounds obtained from the COCONUT database was carried out by pharmacophore mapping, with subsequent dockings and molecular dynamics simulations that resulted in a final selection of 5 hits for inhibiting the cdM2-1 binding site of hRSV. Those hits presented greater structural stability and interaction affinity, with their RMSD, RMSF, radius of gyration, hydrogen bonds, hydrophobic contacts, and free energy of binding analyzed. The ADMET properties were also analyzed and checked for PAINS to discard false-positive results.