Jump to main content
Jump to site search


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

Author affiliations

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.

Graphical abstract: Theoretical models of inhibitory activity for inhibitors of protein–protein interactions: targeting menin–mixed lineage leukemia with small molecules

Back to tab navigation

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, Advance Article
  • Open access: Creative Commons BY-NC license
  •   Request permissions

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

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

    This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements