David L. Mobley

TL;DR: It is shown that the AMOEBA force field is in fact a significant improvement over fixed charge models for small molecule structural and thermodynamic observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small molecules, dynamical properties away from ambient conditions, and possible improvements in aromatic interactions.

TL;DR: An approach to designing tight-binding ligands with a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches is reported, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.

TL;DR: Insights from computational studies of affinities of ligands binding to proteins are reviewed to elucidate how motions and ensembles and alternative conformers and the entropies and forces that cannot be seen in single molecular structures also contribute to binding affinITIES.

TL;DR: Many of the challenges that must be overcome for robust predictions of binding affinity to be useful in rational design are discussed and a number of promising approaches for overcoming them are suggested.

TL;DR: The evidence for severe compensation is found to be weak in light of the large magnitude of and correlation between errors in experimental measurements of entropic and enthalpic contributions to binding, though a limited form of compensation may be common.