Insights from the predicted structural analysis of carborane substituted withaferin A with Indoleamine - 2,3-dioxygenase as a potent inhibitor

Abstract

Indoleamine-2,3-dioxygenase (IDO) an immunoregulatory enzyme and emerging as a new therapeutic drug target for the treatment of cancer. Carboranes, an icosahedral arrangement of eleven boron atoms plus one carbon atom with unique pharmacological properties such low toxicity, isosterism with phenyl ring and stability to hydrolysis. On the other hand, carboranes are known to increase the interaction of ligand with non-polar region of the protein provides an excellent platform to explore these carboranes towards designing and development of novel, potent and target specific drug candidates with further enhanced binding affinities. Despite of their many potential applications, molecular modeling studies of carborane-substituted ligands with macromolecules have been rarely reported. Previously, we have demonstrated the promising high binding affinity of Withaferin-A (WA) for IDO. In this present study, we investigated the effect of carborane substitutions on WA compound towards developing novel analogs for target specific IDO inhibition with better potency. Interesting docked poses and molecular interactions for the carborane substituted WA ligands were elucidated. Based on our In-silico studies, carborane substituted at various position of WA has shown enhanced binding affinity towards IDO, worth of considering for further studies.

Keywords: 3-dioxygenase; Anti-cancer; Carboranes; HOMO; Indoleamine-2; LUMO; Withaferin-A; docking; immunotherapy; molecular dynamic simulations; molecular modeling.

Figure 1

a) HOMO and b) LUMO orbitals of Withaferin A c) designing of derivative Withaferin A compounds with carborane substituted at various positions. d) Docking snapshot of compound 01 showing interactions with heme moiety along with some key residues at the active site of the IDO.

Figure 2

a-g) Simulation event analysis graphs of the IDO in complex with compound 01 h) Molecular interactions network of the compound 01 in complex with IDO during the 25ns simulation time scale.

Figure 3

Molecular interactions of designed compounds 1-10 (a-j) docked inside the binding pocket of IDO.