Designed Tripeptides as Potent NPM1 Oligomerization Inhibitors: A Molecular Docking and Dynamics Study Toward New Anticancer Drug Candidates

Abstract

Inhibition of nucleophosmin enzyme is nowadays considered as a key in many type cancer treatments .Actually researchers investigate (developed)  a significant number of synthetics inhibitors of nucleophosmin enzyme. NPM1 is over-expressed in a number of solid tumours from different histological  origin, this makes it a high targeted protein. However, an efficient inhibitor still a scientific issue. putative small molecular inhibitor SMI (NSC348884) synthetic inhibitors and tripeptides were identified as the most efficient ones.  Currently, molecular modeling presents a powerful procedure to rationalize experimental observations and to design new drugs with desirable activities. In this work, on the basis of the reported NSC348884, and tripeptides, we designed another nine compounds consisting of donor or acceptor moieties and the cyclic conjugation. We studied their interactions with NPM1 and their affinities to binding with the active site using molecular docking. Simulation and modification of theoretical affinities were done using Molecular Operating Environment software (MOE). Obtained results showed numbers of key residues and specific interactions at the binding site of nucleophosmin enzyme; we noted also particularly implication of the Tyrosine 29 amino acid and the presence of the aromatics interactions. As main observation we conclude that Tryptophan-argenine-Tryptophan tripeptide is the most important inhibitor candidate of nucleophosmin enzym among designed molecules.