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强化对抗神经网络计算机用于从头分子设计。

Reinforced Adversarial Neural Computer for de Novo Molecular Design.

机构信息

Pharma.AI Department , Insilico Medicine, Inc , Baltimore , Maryland 21218 , United States.

Computer Technologies Lab , ITMO University , St. Petersburg 197101 , Russia.

出版信息

J Chem Inf Model. 2018 Jun 25;58(6):1194-1204. doi: 10.1021/acs.jcim.7b00690. Epub 2018 Jun 12.


DOI:10.1021/acs.jcim.7b00690
PMID:29762023
Abstract

In silico modeling is a crucial milestone in modern drug design and development. Although computer-aided approaches in this field are well-studied, the application of deep learning methods in this research area is at the beginning. In this work, we present an original deep neural network (DNN) architecture named RANC (Reinforced Adversarial Neural Computer) for the de novo design of novel small-molecule organic structures based on the generative adversarial network (GAN) paradigm and reinforcement learning (RL). As a generator RANC uses a differentiable neural computer (DNC), a category of neural networks, with increased generation capabilities due to the addition of an explicit memory bank, which can mitigate common problems found in adversarial settings. The comparative results have shown that RANC trained on the SMILES string representation of the molecules outperforms its first DNN-based counterpart ORGANIC by several metrics relevant to drug discovery: the number of unique structures, passing medicinal chemistry filters (MCFs), Muegge criteria, and high QED scores. RANC is able to generate structures that match the distributions of the key chemical features/descriptors (e.g., MW, logP, TPSA) and lengths of the SMILES strings in the training data set. Therefore, RANC can be reasonably regarded as a promising starting point to develop novel molecules with activity against different biological targets or pathways. In addition, this approach allows scientists to save time and covers a broad chemical space populated with novel and diverse compounds.

摘要

计算建模是现代药物设计和开发的一个重要里程碑。尽管该领域的计算机辅助方法已经得到了充分研究,但深度学习方法在该研究领域的应用才刚刚开始。在这项工作中,我们提出了一种名为 RANC(强化对抗神经网络计算机)的原始深度神经网络(DNN)架构,用于根据生成对抗网络(GAN)范例和强化学习(RL)从头设计新型小分子有机结构。作为生成器,RANC 使用可微分神经网络(DNC),这是一类神经网络,由于增加了显式存储库,因此具有增强的生成能力,可以减轻对抗环境中常见的问题。比较结果表明,在分子的 SMILES 字符串表示上训练的 RANC 在几个与药物发现相关的指标上优于其第一个基于 DNN 的对应物 ORGANIC:独特结构的数量、通过药物化学筛选(MCFs)、Muegge 标准和高 QED 分数。RANC 能够生成与训练数据集的关键化学特征/描述符(例如 MW、logP、TPSA)和 SMILES 字符串长度的分布匹配的结构。因此,可以合理地认为 RANC 是开发针对不同生物靶标或途径具有活性的新型分子的有前途的起点。此外,这种方法可以让科学家节省时间,并涵盖广泛的化学空间,其中包含新颖多样的化合物。

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