Scoring functions are essential for modern in silico drug discovery. However, the accurate prediction of binding affinity by scoring functions remains a challenging task. The performance of scoring functions is very heterogeneous across different target classes. Scoring functions based on precise physics-based descriptors better representing protein–ligand recognition process are strongly needed. We developed a set of new empirical scoring functions, named DockTScore, by explicitly accounting for physics-based terms combined with machine learning. Target-specific scoring functions were developed for two important drug targets, proteases and protein–protein interactions, representing an original class of molecules for drug discovery. Multiple linear regression (MLR), support vector machine and random forest algorithms were employed to derive general and target-specific scoring functions involving optimized MMFF94S force-field terms, solvation and lipophilic interactions terms, and an improved term accounting for ligand torsional entropy contribution to ligand binding. DockTScore scoring functions demonstrated to be competitive with the current best-evaluated scoring functions in terms of binding energy prediction and ranking on four DUD-E datasets and will be useful for in silico drug design for diverse proteins as well as for specific targets such as proteases and protein–protein interactions. Currently, the MLR DockTScore is available at www.dockthor.lncc.br.

The combination of reinforcement learning with deep learning is a promising approach to tackle important sequential decision-making problems that are currently intractable. One obstacle to overcome is the amount of data needed by learning systems of this type. In this article, we propose to address this issue through a divide-and-conquer approach. We argue that complex decision problems can be naturally decomposed into multiple tasks that unfold in sequence or in parallel. By associating each task with a reward function, this problem decomposition can be seamlessly accommodated within the standard reinforcement-learning formalism. The specific way we do so is through a generalization of two fundamental operations in reinforcement learning: policy improvement and policy evaluation. The generalized version of these operations allow one to leverage the solution of some tasks to speed up the solution of others. If the reward function of a task can be well approximated as a linear combination of the reward functions of tasks previously solved, we can reduce a reinforcement-learning problem to a simpler linear regression. When this is not the case, the agent can still exploit the task solutions by using them to interact with and learn about the environment. Both strategies considerably reduce the amount of data needed to solve a reinforcement-learning problem.

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