论文标题
分子接头设计的模棱两可的3D条件扩散模型
Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design
论文作者
论文摘要
基于碎片的药物发现一直是早期药物开发的有效范式。在该领域的一个开放挑战是设计感兴趣的分子片段之间的接头，以获得化学相关的候选药物分子。在这项工作中，我们提出了Difflinker，一种分子接头设计的E（3） - 等级3D条件扩散模型。给定一组断开的片段，我们的模型将缺失的原子置于两者之间，并设计了包含所有初始片段的分子。与以前只能连接成对分子片段的方法不同，我们的方法可以连接任意数量的片段。此外，该模型会自动确定链接器中的原子数及其在输入片段上的附件。我们证明，Difflinker在标准数据集上的其他方法的表现会产生更多样化和合成的分子。此外，我们在实验中测试了现实世界应用中的方法，表明它可以成功生成以目标蛋白质口袋为条件的有效接头。
Fragment-based drug discovery has been an effective paradigm in early-stage drug development. An open challenge in this area is designing linkers between disconnected molecular fragments of interest to obtain chemically-relevant candidate drug molecules. In this work, we propose DiffLinker, an E(3)-equivariant 3D-conditional diffusion model for molecular linker design. Given a set of disconnected fragments, our model places missing atoms in between and designs a molecule incorporating all the initial fragments. Unlike previous approaches that are only able to connect pairs of molecular fragments, our method can link an arbitrary number of fragments. Additionally, the model automatically determines the number of atoms in the linker and its attachment points to the input fragments. We demonstrate that DiffLinker outperforms other methods on the standard datasets generating more diverse and synthetically-accessible molecules. Besides, we experimentally test our method in real-world applications, showing that it can successfully generate valid linkers conditioned on target protein pockets.
