Molecular docking and dynamics simulations identify marine sponge-derived Halenaquinone as a promising STAT4 modulator for rheumatic heart disease.

This study aimed to investigate the interaction potential of sponge metabolites towards signal transducer and activator of transcription 4 (STAT4), one of the potential targets related with rheumatic heart disease (RHD). Out of 100 sponge molecules screened, Halenaquinone demonstrated as potential inhibitor of STAT4 by modelling. Molecular docking revealed that Halenaquinone exhibited strong binding affinity with STAT4 (-10.2 kcal/mol) and favourable interactions, surpassing the binding of the reference drug Prednisolone-NR3C1complex. The interaction between STAT4 and Halenaquinone stabilized through hydrogen bonding and hydrophobic contacts involving several key residues, supporting its possible inhibitory mechanism. Molecular dynamics simulation studies indicated the stability of the STAT4-Halenaquinone complex, with some flexibility observed in the loop and terminal regions. Free energy decomposition revealed that van der Waals and electrostatic interaction were the main contributors to binding. Furthermore, principal component analysis, dynamic cross correlation and free energy landscape analyses suggested that Halenaquinone binding enhances the conformational adaptability of STAT4, consistent with its role as a potential mediator. The present study provides a computational model of STAT4 as a promising target in RHD and suggests Halenaquinone is a potential marine-sponge-derived compound with therapeutic potential.