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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• CREBBP bromodomains are epigenetic "reader" proteins and targets for cancer therapy.
• Small molecules interacting with CREBBP are influenced by cation-π interactions with arginine residues.

Purpose of the Study:

• To investigate the influence of cation-π interactions on CREBBP binding affinities of small molecules.
• To develop a quantitative model for predicting binding affinity based on molecular interactions.

Main Methods:

• Synthesis and experimental assessment of binding affinities for fifteen 5-isoxazolylbenzimidazole derivatives.
• Computational modeling using Molecular Mechanics (MM) and Quantum Mechanics (QM), including MM-PBSA, MM-GBSA, QM-complexation energies, and Electrostatic Potential Surface (ESP) analysis.

Main Results:

• A strong correlation was found between cation-π interaction strength and CREBBP binding affinity.
• A linear relationship between QM-computed ESP values and cation-π interaction strength yielded the best correlation (R² = 0.84) with experimental binding affinities.
• The QM-ESP model accurately ranked ligand affinities (r_s = 0.91).

Conclusions:

• Electrostatic potential, particularly local substituent effects, is crucial for understanding and predicting cation-π interactions in the CREBBP active site.
• This study provides a quantitative model for predicting non-covalent interaction magnitudes, aiding in the design of novel CREBBP inhibitors for cancer therapy.