论文标题

通过增强学习,从头设计蛋白质目标特定脚手架的抑制剂

De novo design of protein target specific scaffold-based Inhibitors via Reinforcement Learning

论文作者

McNaughton, Andrew D., Bontha, Mridula S., Knutson, Carter R., Pope, Jenna A., Kumar, Neeraj

论文摘要

目标驱动分子的有效设计和发现是促进药物发现中铅优化的关键步骤。目前开发目标蛋白分子的方法是直觉驱动的,由于使用3D结构数据的计算挑战而受到缓慢的迭代设计测试循环的阻碍,最终受到化学家的专业知识的限制 - 导致分子设计的瓶颈。在这项贡献中,我们提出了一个新型框架,称为3D-Molgnn $ _ {RL} $,将增强增强学习(RL)耦合到基于3D-Scaffold的深层生成模型,以生成针对蛋白质构建的目标候选者,从起源核心核心构建原子。 3D-molgnn $ _ {rl} $使用并行图神经网络模型在蛋白质袋中通过多目标奖励功能优化关键功能。该代理商学会了在3D空间中建立分子,同时优化了针对感染性疾病蛋白靶标生成的候选者的活性,结合亲和力,效能和合成可及性。我们的方法可以用作具有优化活性,效力和生物物理特性的铅优化的可解释人工智能(AI)工具。

Efficient design and discovery of target-driven molecules is a critical step in facilitating lead optimization in drug discovery. Current approaches to develop molecules for a target protein are intuition-driven, hampered by slow iterative design-test cycles due to computational challenges in utilizing 3D structural data, and ultimately limited by the expertise of the chemist - leading to bottlenecks in molecular design. In this contribution, we propose a novel framework, called 3D-MolGNN$_{RL}$, coupling reinforcement learning (RL) to a deep generative model based on 3D-Scaffold to generate target candidates specific to a protein building up atom by atom from the starting core scaffold. 3D-MolGNN$_{RL}$ provides an efficient way to optimize key features by multi-objective reward function within a protein pocket using parallel graph neural network models. The agent learns to build molecules in 3D space while optimizing the activity, binding affinity, potency, and synthetic accessibility of the candidates generated for infectious disease protein targets. Our approach can serve as an interpretable artificial intelligence (AI) tool for lead optimization with optimized activity, potency, and biophysical properties.

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