Membrane dynamics simulation and virtual screening reveals potential dual natural inhibitors of endothelin receptors for targeting glaucomatous condition.

Glaucoma is the second leading cause of blindness in the world and is characterized by the loss of retinal ganglion cells (RGC) over a period of time, leading to complete blindness. Recently, endothelin has been identified as an important factor that influences intraocular pressure IOP, OBF, and direct RGC damage. Targeting the endothelin receptor signaling pathway in glaucoma is considered to be highly beneficial, as it can effectively modulate IOP, OBF, and RGC damage, the key factors which are essential to modulate the disease progression holistically. Currently, synthetic drugs like Bosentan, BQ-123, and prostaglandin analogues are available as endothelin receptor antagonists, which are extensively used in the treatment of cardiovascular and other conditions like systemic hypertension. However, the usage of these drugs in glaucoma is limited due to toxicity and poor bioavailability in the ocular milieu. Thus, there is a need for potential natural compounds as endothelin receptor antagonists that acts as dual inhibitors by targeting both ETA and ETB and are highly efficient with the least toxicity. Hence, this study is intended to prioritize endothelin receptor antagonists by structural bioinformatics approaches involving molecular modeling, molecular dynamics, and molecular docking studies. Subsequently, High throughput virtual screening (HTVS) vs. Natural compound databases targeting the optimal binding sites of both ETA and ETB. Following this, the common hits were subjected to binding free energy calculations (MMGBSA) and ADMETox analysis. Finally, the most potential hits were analyzed for MD based binding stability analysis and binding free energy. Similarly, the known synthetic inhibitors were also docked to the receptors and the results were analyzed. From this study, it was inferred that among the natural compounds dataset (8929 compounds), only 4 common compounds were identified as hits. Among these, only one compound ST075640 surpassed all the prioritization criteria including MMGBSA, ADMETox prediction, dual inhibitory potential (ETA & ETB), and also in structural comparative analysis with bosentan it showed similar efficiency. Thus, the validated hit shall prove to be effective in modulating endothelin mediated IOP, OBF, and RGC damage in glaucomatous condition.