Modified Cyclic Tetra-Amino Acid-based Compounds- Potential Human Insulin Degrading Enzyme Inhibitors: Insilico Approach

We examined the effect of electron-withdrawing and donating groups on the biochemical activity of modified cyclic tetra-amino acid-based compounds as human insulin-degrading enzyme inhibitors and predicted a library of drug-like compounds with potent cytotoxicity using an in silico approach. The chosen compounds underwent docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses after being optimized. We found that the hydrogen bond strength between the modified cyclic tetra-amino acid-based compounds and ARG 765 and ASN841, which are positioned in the binding site of the human insulin-degrading enzyme (2g56), was significantly increased upon the addition of propionamide. Also, mutual coordination of methyl (3S,9S,12S)-9-(3-amino-3-oxopropyl)-12-(5-chloro-1,3-dioxoisoindolin-2-yl)-5,8,11-trioxo-4,7,10-triaza-1(1,3)-benzenacyclotridecaphane-3-carboxylate and human insulin-degrading enzyme (2g56) showed enhanced binding propensity with a calculated binding affinity value of -7.96747208 kcal mol-1, compared to other studied molecules. As possible anti-human insulin-degrading enzyme agents, this work may help design and construct a library of effective modified cyclic tetra-amino acid-based compounds.