Abstract
Resistance to small-molecule drugs is the main cause of the failure of therapeutic drugs in clinical practice. Missense mutations altering the binding of ligands to proteins are one of the critical mechanisms that result in genetic disease and drug resistance. Computational methods have made a lot of progress for predicting binding affinity changes and identifying resistance mutations, but their prediction accuracy and speed are still not satisfied and need to be further improved. To address these issues, we introduce a structure-based machine learning method for quantitatively estimating the effects of single mutations on ligand binding affinity changes (named as PremPLI). A comprehensive comparison of the predictive performance of PremPLI with other available methods on two benchmark datasets confirms that our approach performs robustly and presents similar or even higher predictive accuracy than the approaches relying on first-principle statistical mechanics and mixed physics- and knowledge-based potentials while requires much less computational resources. PremPLI can be used for guiding the design of ligand-binding proteins, identifying and understanding disease driver mutations, and finding potential resistance mutations for different drugs. PremPLI is freely available at https://lilab.jysw.suda.edu.cn/research/PremPLI/ and allows to do large-scale mutational scanning.