论文标题

部分可观测时空混沌系统的无模型预测

Tailoring Molecules for Protein Pockets: a Transformer-based Generative Solution for Structured-based Drug Design

论文作者

Wu, Kehan, Xia, Yingce, Fan, Yang, Deng, Pan, Liu, Haiguang, Wu, Lijun, Xie, Shufang, Wang, Tong, Qin, Tao, Liu, Tie-Yan

论文摘要

基于结构的药物设计正在吸引计算机辅助药物发现的注意力。与虚拟筛选方法进行了计算筛选的虚拟筛选方法相比,基于目标蛋白结构的从头筛选的方法设计可以提供新颖的候选药物。在本文中,我们提出了一种名为Tamgent(带有变压器的目标感知分子发生器)的生成溶液,该解决方案可以直接从头开始生成候选药物,以克服现有复合库施加的限制。遵循变压器框架(深度学习中的最新框架),我们设计了变压器编码器的变体,以处理目标的3D几何信息,并预先培训变压器解码器,从PubChem的1000万种化合物中进行候选药物生成。对来自药品银行靶标生成的候选化合物的系统评估表明,结合亲和力和可药用性都得到了很大改善。就有效性和效率而言,坦率的表现优于先前的基线。通过生成SARS-COV-2主蛋白酶和致癌突变体KRAS G12C的候选化合物进一步验证该方法。结果表明,我们的方法不仅重新发现了先前验证的药物分子,而且还产生具有更好的对接得分的新分子,扩展了化合物池并有可能导致发现新药物。

Structure-based drug design is drawing growing attentions in computer-aided drug discovery. Compared with the virtual screening approach where a pre-defined library of compounds are computationally screened, de novo drug design based on the structure of a target protein can provide novel drug candidates. In this paper, we present a generative solution named TamGent (Target-aware molecule generator with Transformer) that can directly generate candidate drugs from scratch for a given target, overcoming the limits imposed by existing compound libraries. Following the Transformer framework (a state-of-the-art framework in deep learning), we design a variant of Transformer encoder to process 3D geometric information of targets and pre-train the Transformer decoder on 10 million compounds from PubChem for candidate drug generation. Systematical evaluation on candidate compounds generated for targets from DrugBank shows that both binding affinity and drugability are largely improved. TamGent outperforms previous baselines in terms of both effectiveness and efficiency. The method is further verified by generating candidate compounds for the SARS-CoV-2 main protease and the oncogenic mutant KRAS G12C. The results show that our method not only re-discovers previously verified drug molecules , but also generates novel molecules with better docking scores, expanding the compound pool and potentially leading to the discovery of novel drugs.

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