A fully differentiable ligand pose optimization framework guided by deep learning and traditional scoring functions

The machine learning (ML) and deep learning (DL) techniques are widely recognized to be powerful tools for virtual drug screening. The recently reported ML- or DL-based scoring functions have shown exciting performance in predicting protein-ligand binding affinities with fruitful application prospects. However, the differentiation between highly similar ligand conformations, including the native binding pose (the global energy minimum state), remains challenging which could greatly enhance the docking. In this work, we propose a fully differentiable framework for ligand pose optimization based on a hybrid scoring function (SF) combined with a multi-layer perceptron (DeepRMSD) and the traditional AutoDock Vina SF. The DeepRMSD+Vina, which combines (1) the root mean square deviation (RMSD) of the docking pose with respect to the native pose and (2) the AutoDock Vina score, is fully differentiable thus is capable of optimizing the ligand binding pose to the energy-lowest conformation. Evaluated by the CASF-2016 docking power dataset, the DeepRMSD+Vina reaches a success rate of 95.4%, which is by far the best reported SF to date. Based on this SF, an end-to-end ligand pose optimization framework was implemented to improve the docking pose quality. We demonstrated that this method significantly improves the docking success rate (by 15%) in redocking and crossdocking tasks, revealing the high potentialities of this framework in drug design and discovery.