In-silico exploration of potential indoleamine 2,3-dioxygenase-1 inhibitors: An insight from docking, ADME and molecular dynamic simulations

Abstract

Indoleamine-2,3-dioxygenase-1 (IDO1) catalysed tryptophan-kynurenine (Tyr-Kyn) pathway is essential for regulating various biological processes, including metabolism and immune responses. Recent reports on activation of Tyr-Kyn pathway during COVID-19 infection also highlights the significance of IDO 1 inhibition a new therapeutic target for treating complications of COVID-19. Consequently, IDO1 inhibitors are seen as emerging molecules for cancer therapy and several other diseases. There is a pressing need for development of novel potential IDO 1 inhibitors. The current study reports an identification of potential IDO1 inhibitors from library of reported IDO1 inhibitors (265 molecules) belonging to 32 categories/scaffolds. Initially molecular docking was carried out on the selected 265 molecules and are subsequently compared with reference drug Epacadostat. The result of the top 24 molecules with high D scores were compared with the reference (Epacadostat) and screened sequentially by ADME filters to find out a possible drug candidate(s). Furthermore, simulations for the stability determination, calculation of free energy of the binding was done on the four ligand-pocket complexes (8, 43, 66, and 243) in order to find the dynamic properties and confirm the docking results. Among four molecules, docking results of 243 and 43 ligands were found in agreement with the experimentally obtained results, and these compounds demonstrated to have potent activity and selectivity for IDO1 enzyme. The findings are useful and supportive and warrant further biological evaluation of potential IDO1 inhibitors 243 and 43.