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.

Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19

“…The MM/PBSA (Molecular Mechanics/Poisson–Boltzmann Surface Area) methodology began with reports from Kollman and co-workers, but more recent developmental efforts have provided an important tool for studying ligand binding on various biological systems. 35 It is one of the robust method that has been successfully applied to estimate the free energy of binding for inhibitors with small or large differences in the principle scaffold, 57 chiral compounds 55 and small peptides. 58 In this work, the binding affinity of Kobophenol A in the ACE2 pocket and the ACE2/spike interface was calculated using the MM/PBSA approach available within the Amber package ( eqs 1 - 6 ), where − E gas is the standard energy term in molecular mechanics for bonded and nonbonded integrations, and G pol and G np are the polar and nonpolar contribution states of the solvation free energy (Δ G solvation ), respectively.…”