The physics-AI dialogue in drug design

Abstract

A long path has led from the determination of the first protein structure in 1960 to the recent breakthroughs in protein science. Protein structure prediction and design methodologies based on machine learning (ML) have been recognized with the 2024 Nobel prize in Chemistry, but they would not have been possible without previous work and the input of many domain scientists. Challenges remain in the application of ML tools for the prediction of structural ensembles and their usage within the software pipelines for structure determination by crystallography or cryogenic electron microscopy. In the drug discovery workflow, ML techniques are being used in diverse areas such as scoring of docked poses, or the generation of molecular descriptors. As the ML techniques become more widespread, novel applications emerge which can profit from the large amounts of data available. Nevertheless, it is essential to balance the potential advantages against the environmental costs of ML deployment to decide if and when it is best to apply it. For hit to lead optimization ML tools can efficiently interpolate between compounds in large chemical series but free energy calculations by molecular dynamics simulations seem to be superior for designing novel derivatives. Importantly, the potential complementarity and/or synergism of physics-based methods (e.g., force field-based simulation models) and data-hungry ML techniques is growing strongly. Current ML methods have evolved from decades of research. It is now necessary for biologists, physicists, and computer scientists to fully understand advantages and limitations of ML techniques to ensure that the complementarity of physics-based methods and ML tools can be fully exploited for drug design.