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

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 + E_Das) produced a remarkable correlation with experimentally measured inhibitory activities and enabled accurate activity pre

SUBMITTER: Jedwabny W 

PROVIDER: S-EPMC5774433 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature