Jump to main content
Jump to site search
PLANNED MAINTENANCE Close the message box

Scheduled maintenance work on Wednesday 27th March 2019 from 11:00 AM to 1:00 PM (GMT).

During this time our website performance may be temporarily affected. We apologise for any inconvenience this might cause and thank you for your patience.


Issue 46, 2016
Previous Article Next Article

Cation–π interactions in CREBBP bromodomain inhibition: an electrostatic model for small-molecule binding affinity and selectivity

Author affiliations

Abstract

CREBBP bromodomains, epigenetic “reader” proteins that recognize acetylated histone lysine residues, are a current target for cancer therapy. We show that experimental CREBBP binding affinities of small-molecules with aromatic or heteroaromatic functional groups are strongly influenced by a cation–π interaction with a positively charged arginine residue. For a series of fifteen 5-isoxazolylbenzimidazole derivatives, the strength of this non-covalent interaction is directly related to improvements in binding to CREBBP. The aromatic substituents’ inductive and resonance effects are not obviously correlated with observed structure and affinity relationships. In contrast, a coulombic electrostatic model can quantitatively predict the interaction strength. We have assessed different Molecular Mechanics (MM) and Quantum Mechanics (QM) descriptions of the protein–ligand interaction. Quantitative models for binding affinity were generated from: (1) Poisson Boltzmann Surface Area (MM-PBSA) and Generalized Born Surface Area (MM-GBSA) scoring functions that incorporated the entire ligand and (2) QM-complexation energies and (3) Electrostatic Potential Surface values (ESPs) that analyzed the varying aromatic group. A linear relationship between QM-computed ESP values is established for the cation–π interaction strength, and gives the best correlation (R2 = 0.84) with experimental binding affinities. This model also ranks ligand affinity most accurately (rs = 0.91) from the models tested. Consideration of the electrostatic potential in response to the local effects of substituents in addition to that of the aromatic ring is necessary to understand and describe the interaction with the cationic guanidinium ion. This leads to an improved understanding and the ability to quantitatively predict the magnitude of non-covalent interactions in the CREBBP active site.

Graphical abstract: Cation–π interactions in CREBBP bromodomain inhibition: an electrostatic model for small-molecule binding affinity and selectivity

Back to tab navigation

Supplementary files

Publication details

The article was received on 13 Oct 2016, accepted on 26 Oct 2016 and first published on 26 Oct 2016


Article type: Paper
DOI: 10.1039/C6OB02234K
Citation: Org. Biomol. Chem., 2016,14, 10926-10938

  •   Request permissions

    Cation–π interactions in CREBBP bromodomain inhibition: an electrostatic model for small-molecule binding affinity and selectivity

    W. A. Cortopassi, K. Kumar and R. S. Paton, Org. Biomol. Chem., 2016, 14, 10926
    DOI: 10.1039/C6OB02234K

Search articles by author

Spotlight

Advertisements