Understanding and quantifying protein-ligand interactions is a key step of the drug discovery process. However, obtaining a reliable correlation between binding and activity that can be used with predictive power is still an active area of research. This is because most ranking and scoring methods are based on classical-mechanics approximations and hence, the underlying level of theory may not be adequate for describing the intrinsic nature of protein-ligand interactions or desolvation effects. In this work, we apply a high-level <i>ab initio</i> method to predict relative binding energies, based on a quantum-mechanical description of the ligand and the surrounding residues in combination with a classical-mechanics treatment of the remaining environment. Our results suggest QM/MM scoring is better suited for ranking congeneric ligand series where induced fit effects are smaller. On average, QM/MM scores are better than those based on classical mechanics alone and are comparable to the state-of-the-art FEP scoring implementation.<br/>

Correlating protein-ligand activity to quantum-mechanics/molecular-mechanics binding energies

254th National Meeting (2017)

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