论文标题

支架约束的分子产生

Scaffold-constrained molecular generation

论文作者

Langevin, Maxime, Minoux, Herve, Levesque, Maximilien, Bianciotto, Marc

论文摘要

生成模型在药物发现中的主要应用之一是铅优化阶段。在优化铅系列的过程中,通常对设计分子的结构施加脚手架约束。在没有执行此类约束的情况下,用所需支架产生分子的可能性极低,并且阻碍了De-Novo药物设计的生成模型的实用性。为了解决这个问题,我们引入了一种新算法,以执行脚手架内部分子设计。我们建立在众所周知的基于微笑的复发性神经网络(RNN)生成模型的基础上,并采用了修改的采样程序,以实现支架受限的生成。我们直接受益于相关的增强学习方法,从而可以设计针对不同特性优化的分子,同时仅探索相关的化学空间。我们展示了该方法在各种任务上执行脚手架约束生成的能力:在Surechembl化学系列中提取的脚手架上设计新颖的分子,在多巴胺受体D2(DRD2)目标上产生新颖的活性分子,最后,在MMP-12系列上设计了预测的活性剂,该系列是MMP-12系列,一个工业铅铅技术。

One of the major applications of generative models for drug Discovery targets the lead-optimization phase. During the optimization of a lead series, it is common to have scaffold constraints imposed on the structure of the molecules designed. Without enforcing such constraints, the probability of generating molecules with the required scaffold is extremely low and hinders the practicality of generative models for de-novo drug design. To tackle this issue, we introduce a new algorithm to perform scaffold-constrained in-silico molecular design. We build on the well-known SMILES-based Recurrent Neural Network (RNN) generative model, with a modified sampling procedure to achieve scaffold-constrained generation. We directly benefit from the associated reinforcement Learning methods, allowing to design molecules optimized for different properties while exploring only the relevant chemical space. We showcase the method's ability to perform scaffold-constrained generation on various tasks: designing novel molecules around scaffolds extracted from SureChEMBL chemical series, generating novel active molecules on the Dopamine Receptor D2 (DRD2) target, and, finally, designing predicted actives on the MMP-12 series, an industrial lead-optimization project.

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