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

Abstract

The concept of activity cliff (AC) (i.e., a small structural modification resulting in a substantial bioactivity change) is widely encountered in medicinal chemistry during compound design. Whereas the study of ACs is of high interest as it provides a wealth of opportunities for effective drug design, its practical application in the actual drug development process has been difficult because of significant computational challenges. To provide some understanding of the ACs, we have carried out a rigorous quantum-mechanical investigation of the electronic interactions of a wide range of ACs (205 cliffs formed by 261 protein-ligand complexes covering 37 different receptor types) using multilayer molecules-in-molecules (MIM) fragmentation-based methodology. The MIM methodology enables performing accurate high-level quantum mechanical (QM) calculations at a substantially lower computational cost, while allowing for a quantitative decomposition of the protein-ligand binding energy into the contributions from individual residues, solvation, and entropy. Our investigation in this study is mainly focused on whether the QM binding energy calculation can correctly identify the higher potency cliff partner for a given ligand pair having a sufficiently high activity difference. We have also analyzed the effect of including crystal water molecules as a part of the receptor as well as the impact of ligand desolvation energy on the correct identification of the more potent ligand in a cliff pair. Our analysis reveals that, in the majority of the cases, the AC prediction could be significantly improved by carefully identifying the critical crystal water molecules, whereas the contribution from the ligand desolvation also remains essential. Additionally, we have exploited the residue-specific interaction energies provided by MIM to identify the key residues and interaction hot-spots that are responsible for the experimentally observed drastic activity changes. The results show that our MIM fragmentation-based protocol provides comprehensive interaction energy profiles that can be employed to understand the distinctiveness of ligand modifications, for potential applications in structure-based drug design.