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通过使用深度神经网络捕捉化学家的直觉进行分子优化。

Molecular optimization by capturing chemist's intuition using deep neural networks.

作者信息

He Jiazhen, You Huifang, Sandström Emil, Nittinger Eva, Bjerrum Esben Jannik, Tyrchan Christian, Czechtizky Werngard, Engkvist Ola

机构信息

Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

出版信息

J Cheminform. 2021 Mar 20;13(1):26. doi: 10.1186/s13321-021-00497-0.

Abstract

A main challenge in drug discovery is finding molecules with a desirable balance of multiple properties. Here, we focus on the task of molecular optimization, where the goal is to optimize a given starting molecule towards desirable properties. This task can be framed as a machine translation problem in natural language processing, where in our case, a molecule is translated into a molecule with optimized properties based on the SMILES representation. Typically, chemists would use their intuition to suggest chemical transformations for the starting molecule being optimized. A widely used strategy is the concept of matched molecular pairs where two molecules differ by a single transformation. We seek to capture the chemist's intuition from matched molecular pairs using machine translation models. Specifically, the sequence-to-sequence model with attention mechanism, and the Transformer model are employed to generate molecules with desirable properties. As a proof of concept, three ADMET properties are optimized simultaneously: logD, solubility, and clearance, which are important properties of a drug. Since desirable properties often vary from project to project, the user-specified desirable property changes are incorporated into the input as an additional condition together with the starting molecules being optimized. Thus, the models can be guided to generate molecules satisfying the desirable properties. Additionally, we compare the two machine translation models based on the SMILES representation, with a graph-to-graph translation model HierG2G, which has shown the state-of-the-art performance in molecular optimization. Our results show that the Transformer can generate more molecules with desirable properties by making small modifications to the given starting molecules, which can be intuitive to chemists. A further enrichment of diverse molecules can be achieved by using an ensemble of models.

摘要

药物研发中的一个主要挑战是找到具有多种性质理想平衡的分子。在此,我们专注于分子优化任务,其目标是将给定的起始分子优化至具有理想性质。该任务可被构建为自然语言处理中的机器翻译问题,在我们的案例中,一个分子基于SMILES表示被翻译成具有优化性质的分子。通常,化学家会运用他们的直觉为正在优化的起始分子建议化学转化。一种广泛使用的策略是匹配分子对的概念,即两个分子仅相差一个转化。我们试图使用机器翻译模型从匹配分子对中捕捉化学家的直觉。具体而言,采用带有注意力机制的序列到序列模型以及Transformer模型来生成具有理想性质的分子。作为概念验证,同时优化了三个ADMET性质:logD、溶解度和清除率,这些都是药物的重要性质。由于理想性质往往因项目而异,用户指定的理想性质变化作为附加条件与正在优化的起始分子一起纳入输入。这样,模型就能被引导生成满足理想性质的分子。此外,我们基于SMILES表示将这两个机器翻译模型与图到图翻译模型HierG2G进行比较,HierG2G在分子优化方面已展现出最先进的性能。我们的结果表明,Transformer通过对给定的起始分子进行微小修改能够生成更多具有理想性质的分子,这对化学家来说可能是直观的。通过使用模型集成可以进一步实现多样分子的富集。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5af4/7980633/83c639be467c/13321_2021_497_Fig1_HTML.jpg

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