Abstract
<jats:p>Tryptophan residues shape protein-ligand recognition through steric volume, dispersion, aromatic contacts, and indole-NH interactions. We used W730A to probe how loss of these features alters the Nipah virus polymerase inhibitor pocket and compared BMS-986205 with the structure-bound inhibitor ERDRP-0519. A 100-compound screen supplied selection context, while paired docking defined starting poses for explicit-solvent molecular dynamics of each ligand with WT and W730A polymerase. We analyzed ligand displacement, protein and pocket motion, interaction fingerprints, geometry-event occupancies, and MM-GBSA endpoint estimates. BMS-986205/W730A showed the lowest mean displacement from its case-specific reference pose (1.86 Å). ERDRP-0519 produced more-negative raw MM-GBSA estimates in both receptor states. W730A also altered static contact annotations and residue-level endpoint terms in a ligand-dependent manner. We observed distinct changes in local molecular recognition for the two chemotypes after removal of W730 indole chemistry. We therefore propose BMS-986205 as a structural probe of W730A-dependent pocket remodeling and define contact and binding hypotheses for experimental follow-up.</jats:p>