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arXiv 2306.08166cs.LGcs.AIq-bio.BM
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基于快速注意力机制点云对齐的强化学习驱动连接子设计

Reinforcement Learning-Driven Linker Design via Fast Attention-based Point Cloud Alignment

VantAI(VantAI公司)

Rebecca M. Neeser, Mehmet Akdel, Daniel Kovtun, Luca Naef

AI总结:

针对PROTAC连接子设计的几何化学约束及类药性优化难题,提出ShapeLinker方法,结合强化学习与注意力点云对齐评分,实现满足2D/3D要求的新型连接子生成,达到当前最优水平。

摘要:

蛋白水解靶向嵌合体(PROTACs)是一类新型小分子,被设计用作E3连接酶与疾病相关蛋白之间的桥梁,从而促进靶蛋白的后续降解。PROTAC由两个蛋白结合“活性”结构域组成,二者通过一个“连接子”结构域相连。连接子结构域的设计颇具挑战,因为其相互作用存在几何与化学约束,且需要最大化类药性。为应对这些挑战,我们提出ShapeLinker,一种从头设计连接子的方法。它在自回归SMILES生成器上利用强化学习执行片段连接。该方法优化一个综合评分,该评分结合了相关理化性质与一种新型的基于注意力的点云对齐评分。这一新方法成功生成了同时满足相关2D和3D要求的连接子,并且在给定目标连接子构象的前提下,在生成新型连接子方面取得了当前最优结果。这使得PROTAC的设计与优化更具合理性与效率。代码和数据可在https://github.com/aivant/ShapeLinker获取。

英文摘要:

Proteolysis-Targeting Chimeras (PROTACs) represent a novel class of small molecules which are designed to act as a bridge between an E3 ligase and a disease-relevant protein, thereby promoting its subsequent degradation. PROTACs are composed of two protein binding "active" domains, linked by a "linker" domain. The design of the linker domain is challenging due to geometric and chemical constraints given by its interactions, and the need to maximize drug-likeness. To tackle these challenges, we introduce ShapeLinker, a method for de novo design of linkers. It performs fragment-linking using reinforcement learning on an autoregressive SMILES generator. The method optimizes for a composite score combining relevant physicochemical properties and a novel, attention-based point cloud alignment score. This new method successfully generates linkers that satisfy both relevant 2D and 3D requirements, and achieves state-of-the-art results in producing novel linkers assuming a target linker conformation. This allows for more rational and efficient PROTAC design and optimization. Code and data are available at https://github.com/aivant/ShapeLinker.

机构、总结、中文摘要均由AI分析而来,可能存在错误,请以论文正文为准。

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