TCS Research (Life Sciences Division), Tata Consultancy Services Limited, Hyderabad 500081, India.
J Chem Inf Model. 2022 Nov 14;62(21):5100-5109. doi: 10.1021/acs.jcim.1c01319. Epub 2021 Nov 18.
In recent years, deep learning-based methods have emerged as promising tools for drug design. Most of these methods are ligand-based, where an initial target-specific ligand data set is necessary to design potent molecules with optimized properties. Although there have been attempts to develop alternative ways to design target-specific ligand data sets, availability of such data sets remains a challenge while designing molecules against novel target proteins. In this work, we propose a deep learning-based method, where the knowledge of the active site structure of the target protein is sufficient to design new molecules. First, a graph attention model was used to learn the structure and features of the amino acids in the active site of proteins that are experimentally known to form protein-ligand complexes. Next, the learned active site features were used along with a pretrained generative model for conditional generation of new molecules. A bioactivity prediction model was then used in a reinforcement learning framework to optimize the conditional generative model. We validated our method against two well-studied proteins, Janus kinase 2 (JAK2) and dopamine receptor D2 (DRD2), where we produce molecules similar to the known inhibitors. The graph attention model could identify the probable key active site residues, which influenced the conditional molecule generator to design new molecules with pharmacophoric features similar to the known inhibitors.
近年来,基于深度学习的方法已成为药物设计有前途的工具。这些方法大多是基于配体的,其中需要初始的针对特定目标的配体数据集来设计具有优化性质的有效分子。尽管已经有尝试开发替代方法来设计针对特定目标的配体数据集,但在针对新型靶蛋白设计分子时,此类数据集的可用性仍然是一个挑战。在这项工作中,我们提出了一种基于深度学习的方法,其中只需目标蛋白的活性位点结构的知识即可设计新分子。首先,使用图注意模型来学习实验上已知形成蛋白-配体复合物的蛋白质的活性位点中氨基酸的结构和特征。接下来,使用学习到的活性位点特征以及预训练的生成模型,对新分子进行条件生成。然后,使用生物活性预测模型在强化学习框架中对条件生成模型进行优化。我们针对两种研究充分的蛋白质 Janus 激酶 2 (JAK2)和多巴胺受体 D2 (DRD2) 对我们的方法进行了验证,生成的分子与已知抑制剂相似。图注意模型可以识别可能的关键活性位点残基,这些残基影响条件分子生成器来设计具有与已知抑制剂相似药效特征的新分子。