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基于结构的药物设计与等变扩散模型

Structure-based drug design with equivariant diffusion models.

作者信息

Schneuing Arne, Harris Charles, Du Yuanqi, Didi Kieran, Jamasb Arian, Igashov Ilia, Du Weitao, Gomes Carla, Blundell Tom L, Lio Pietro, Welling Max, Bronstein Michael, Correia Bruno

机构信息

École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

University of Cambridge, Cambridge, UK.

出版信息

Nat Comput Sci. 2024 Dec;4(12):899-909. doi: 10.1038/s43588-024-00737-x. Epub 2024 Dec 9.

Abstract

Structure-based drug design (SBDD) aims to design small-molecule ligands that bind with high affinity and specificity to pre-determined protein targets. Generative SBDD methods leverage structural data of drugs with their protein targets to propose new drug candidates. However, most existing methods focus exclusively on bottom-up de novo design of compounds or tackle other drug development challenges with task-specific models. The latter requires curation of suitable datasets, careful engineering of the models and retraining from scratch for each task. Here we show how a single pretrained diffusion model can be applied to a broader range of problems, such as off-the-shelf property optimization, explicit negative design and partial molecular design with inpainting. We formulate SBDD as a three-dimensional conditional generation problem and present DiffSBDD, an SE(3)-equivariant diffusion model that generates novel ligands conditioned on protein pockets. Furthermore, we show how additional constraints can be used to improve the generated drug candidates according to a variety of computational metrics.

摘要

基于结构的药物设计(SBDD)旨在设计与预先确定的蛋白质靶点具有高亲和力和特异性结合的小分子配体。生成式SBDD方法利用药物与其蛋白质靶点的结构数据来提出新的药物候选物。然而,大多数现有方法仅专注于化合物的自下而上的从头设计,或使用特定任务模型来解决其他药物开发挑战。后者需要策划合适的数据集、精心设计模型并针对每个任务从头重新训练。在这里,我们展示了如何将单个预训练的扩散模型应用于更广泛的问题,例如现成的性质优化、显式负设计和带有图像修复的部分分子设计。我们将SBDD表述为三维条件生成问题,并提出DiffSBDD,这是一种基于蛋白质口袋条件生成新型配体的SE(3)等变扩散模型。此外,我们展示了如何根据各种计算指标使用额外的约束来改进生成的药物候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf40/11659159/b83e6700c156/43588_2024_737_Fig1_HTML.jpg

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