Document Report Card

ID: ALA4261532

Journal: Medchemcomm

Title: Theoretical models of inhibitory activity for inhibitors of protein-protein interactions: targeting menin-mixed lineage leukemia with small molecules.

Authors: Jedwabny W, Kłossowski S, Purohit T, Cierpicki T, Grembecka J, Dyguda-Kazimierowicz E.

Abstract: Development and binding affinity predictions of inhibitors targeting protein-protein interactions (PPI) still represent a major challenge in drug discovery efforts. This work reports application of a predictive non-empirical model of inhibitory activity for PPI inhibitors, exemplified here for small molecules targeting the menin-mixed lineage leukemia (MLL) interaction. Systematic ab initio analysis of menin-inhibitor complexes was performed, revealing the physical nature of these interactions. Notably, the non-empirical protein-ligand interaction energy comprising electrostatic multipole and approximate dispersion terms (E(10)El,MTP + EDas) produced a remarkable correlation with experimentally measured inhibitory activities and enabled accurate activity prediction for new menin-MLL inhibitors. Importantly, this relatively simple and computationally affordable non-empirical interaction energy model outperformed binding affinity predictions derived from commonly used empirical scoring functions. This study demonstrates high relevance of the non-empirical model we developed for binding affinity prediction of inhibitors targeting protein-protein interactions that are difficult to predict using empirical scoring functions.

CiteXplore: 29456828

DOI: 10.1039/C7MD00170C