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基于潜在强化学习的靶向分子生成

Targeted molecular generation with latent reinforcement learning.

作者信息

Haddad Ragy, Litsa Eleni E, Liu Zhen, Yu Xin, Burkhardt Daniel, Bhisetti Govinda

机构信息

Cellarity, Inc, Somerville, USA.

Carnegie Mellon University, Pittsburgh, USA.

出版信息

Sci Rep. 2025 Apr 30;15(1):15202. doi: 10.1038/s41598-025-99785-0.

Abstract

Computational methods for generating molecules with specific physiochemical properties or biological activity can greatly assist drug discovery efforts. Deep learning generative models constitute a significant step towards that direction. We introduce a novel approach that utilizes a Reinforcement Learning paradigm, called proximal policy optimization, for optimizing molecules in the latent space of a pretrained generative model. Working in the latent space of a generative model lets us bypass the need for explicitly defining chemical rules when computationally designing molecules. The generation of molecules is achieved through navigating the latent space for identifying regions that correspond to molecules with desired properties. Proximal policy optimization is a state-of-the-art policy gradient algorithm capable of operating in continuous high-dimensional spaces in a sample-efficient manner. We have paired our optimization framework with the latent spaces of two different architectures of autoencoder models showing that the method is agnostic to the underlying architecture. We present results on commonly used benchmarks for molecule optimization that demonstrate that our method has comparable or even superior performance to state-of-the-art approaches. We additionally show how our method can generate molecules that contain a pre-specified substructure while simultaneously optimizing for molecular properties, a task highly relevant to real drug discovery scenarios.

摘要

生成具有特定物理化学性质或生物活性分子的计算方法可以极大地助力药物发现工作。深度学习生成模型朝着这个方向迈出了重要一步。我们引入了一种新颖的方法,该方法利用一种名为近端策略优化的强化学习范式,在预训练生成模型的潜在空间中优化分子。在生成模型的潜在空间中工作使我们在通过计算设计分子时无需明确定义化学规则。分子的生成是通过在潜在空间中导航来识别与具有所需性质的分子相对应的区域来实现的。近端策略优化是一种先进的策略梯度算法,能够以样本高效的方式在连续高维空间中运行。我们已将优化框架与两种不同架构的自动编码器模型的潜在空间相结合,表明该方法与基础架构无关。我们展示了在分子优化常用基准测试中的结果,证明我们的方法与现有方法具有可比甚至更优的性能。我们还展示了我们的方法如何生成包含预先指定子结构的分子,同时针对分子性质进行优化,这是一项与实际药物发现场景高度相关的任务。

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