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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 represents a major challenge in drug discovery efforts. This work reports application of the predictive nonempirical model of inhibitory activity for PPI inhibitors, exemplified here for small molecules targeting the menin-Mixed Lineage Leukemia (MLL) interaction. The systematic ab initio analysis of the menin-inhibitor complexes was performed, revealing the physical nature of these interactions. Notably, the nonempirical 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 nonempirical interaction energy model outperformed binding affinity predictions derived from the commonly used empirical scoring functions. This study demonstrates high relevance of the nonempirical model we developed for binding affinity prediction of inhibitors targeting protein-protein interactions that are difficult to predict using empirical scoring functions.

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Supplementary files

Publication details

The article was received on 07 Apr 2017, accepted on 06 Sep 2017 and first published on 12 Sep 2017


Article type: Research Article
DOI: 10.1039/C7MD00170C
Citation: Med. Chem. Commun., 2017, Accepted Manuscript
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    Theoretical models of inhibitory activity for inhibitors of protein-protein interactions: targeting menin-Mixed Lineage Leukemia with small molecules

    W. Jedwabny, S. Klossowski, T. Purohit, T. Cierpicki, J. Grembecka and E. Dyguda-Kazimierowicz, Med. Chem. Commun., 2017, Accepted Manuscript , DOI: 10.1039/C7MD00170C

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