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

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 (R = 0.84) with experimental binding affinities. This model also ranks ligand affinity most accurately (r = 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.

Cation–π interactions in protein–ligand binding: theory and data-mining reveal different roles for lysine and arginine

“…1C ). 25 – 27 Predictable structure–activity relationships were established according to the electrostatic interaction strength. 27 …”

XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer

“…The bottom pyridine ring of the CBP complex rotates 90°, as CBP lacks the Trp for a pi–pi interaction in the LPF pocket. However, XP-524 forms a cation–pi interaction with Arg-1173, a key interaction in the design of potent EP300/CBP inhibitors ( 26 – 28 ). Contrastingly, JQ-1 is not able to capture this important cation–pi interaction, as the chlorophenyl ring of JQ-1 clashes with Arg-1173, thereby blocking the binding of JQ-1 to CBP and the ability of JQ-1 to act as an EP300/CBP inhibitor ( Fig.…”

Complexation Energies and Electronic-Structural Properties of Adamantane Derivatives: A DFT Study

“…Gap between corrected and raw complexation energy is equal to BSSE energy. In all CP calculations empirical dispersion method, D2 version of Grimme's dispersion correction [35], was applied with B3LYP and WB97XD by defining the values of the functional-specific global parameters for non-covalent interactions [36,37].…”