Quantum Mechanical Investigation of Three-Dimensional Activity Cliffs Using the Molecules-in-Molecules...

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Design

Background:

• Activity cliffs (ACs) represent small structural changes leading to significant bioactivity shifts, offering drug design opportunities.
• Computational challenges have historically limited the practical application of AC studies in drug development.

Purpose of the Study:

• To investigate the utility of quantum mechanical (QM) binding energy calculations in identifying the more potent partner in activity cliff pairs.
• To assess the impact of crystal water molecules and ligand desolvation on AC prediction accuracy.

Main Methods:

• Utilized multilayer molecules-in-molecules (MIM) fragmentation for rigorous QM calculations on 205 ACs across 37 receptor types.
• Decomposed protein-ligand binding energy into residue-specific, solvation, and entropic contributions.
• Analyzed the influence of crystal waters and ligand desolvation on predicting higher potency cliff partners.

Main Results:

• QM binding energy calculations, particularly with MIM, can correctly identify higher potency AC partners.
• Incorporating critical crystal water molecules significantly improves AC prediction.
• Ligand desolvation energy is essential for accurate identification of the more potent ligand.

Conclusions:

• The MIM fragmentation approach provides accurate QM binding energies for AC analysis.
• This method enables detailed understanding of residue-specific interactions driving activity changes.
• The developed protocol enhances structure-based drug design by elucidating ligand modification effects.