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基于 3D 相似度评分的深度生成模型从头设计。

De novo design with deep generative models based on 3D similarity scoring.

机构信息

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

Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK.

出版信息

Bioorg Med Chem. 2021 Aug 15;44:116308. doi: 10.1016/j.bmc.2021.116308. Epub 2021 Jul 9.

Abstract

We have demonstrated the utility of a 3D shape and pharmacophore similarity scoring component in molecular design with a deep generative model trained with reinforcement learning. Using Dopamine receptor type 2 (DRD2) as an example and its antagonist haloperidol 1 as a starting point in a ligand based design context, we have shown in a retrospective study that a 3D similarity enabled generative model can discover new leads in the absence of any other information. It can be efficiently used for scaffold hopping and generation of novel series. 3D similarity based models were compared against 2D QSAR based, indicating a significant degree of orthogonality of the generated outputs and with the former having a more diverse output. In addition, when the two scoring components are combined together for training of the generative model, it results in more efficient exploration of desirable chemical space compared to the individual components.

摘要

我们已经证明了在分子设计中使用强化学习训练的深度生成模型的 3D 形状和药效团相似性评分组件的实用性。以多巴胺受体 2(DRD2)及其拮抗剂氟哌啶醇 1 为例,在基于配体的设计背景下,我们在回顾性研究中表明,具有 3D 相似性的生成模型可以在没有任何其他信息的情况下发现新的先导化合物。它可以有效地用于支架跃迁和新系列的生成。将基于 3D 相似性的模型与基于 2D QSAR 的模型进行了比较,表明生成的输出具有显著的正交性,并且前者的输出更加多样化。此外,当将这两个评分组件结合在一起用于生成模型的训练时,与单独的组件相比,它可以更有效地探索理想的化学空间。

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