TargetSA: Adaptive Simulated Annealing for Target-Specific Drug Design.

Abstract

The burgeoning field of target-specific drug design has attracted considerable attention, focusing on identifying compounds with high binding affinity towards specific target pockets. Nevertheless, existing target-specific deep generative models encounter notable challenges. Some models heavily rely on elaborate datasets and complicated training methodologies, while others neglect the multi-constraint optimization problem inherent in drug design, resulting in generated molecules with irrational structures or chemical properties. To address these issues, we propose a novel framework (TargetSA) that leverages adaptive simulated annealing (SA) for target-specific molecular generation and multi-constraint optimization. SA process explores the discrete structural space of molecules, progressively converging toward the optimal to fulfill the predefined objective. To propose novel compounds, we first predict promising editing positions based on historical experience, and then iteratively edit molecular graphs through four operations (insertion, replacement, deletion, and cyclization). Together, these operations collectively constitute a complete operation set, facilitating a thorough exploration of the drug-like space. Furthermore, we introduce a reversible sampling strategy to re-accept currently suboptimal solutions, greatly enhancing the generation quality. Empirical evaluations demonstrate that TargetSA achieves state-of-the-art performance in generating high-affinity molecules (Average Vina Dock -9.09) while maintaining desirable chemical properties. https://github.com/XueZhe-Zachary/TargetSA. More implementation details and experiments are in the Supplementary Materials.