City University of Hong Kong, Hong Kong, SAR, China.
Tencent AI Lab, Shenzhen, China.
Nat Commun. 2024 Mar 26;15(1):2657. doi: 10.1038/s41467-024-46569-1.
Structure-based generative chemistry is essential in computer-aided drug discovery by exploring a vast chemical space to design ligands with high binding affinity for targets. However, traditional in silico methods are limited by computational inefficiency, while machine learning approaches face bottlenecks due to auto-regressive sampling. To address these concerns, we have developed a conditional deep generative model, PMDM, for 3D molecule generation fitting specified targets. PMDM consists of a conditional equivariant diffusion model with both local and global molecular dynamics, enabling PMDM to consider the conditioned protein information to generate molecules efficiently. The comprehensive experiments indicate that PMDM outperforms baseline models across multiple evaluation metrics. To evaluate the applications of PMDM under real drug design scenarios, we conduct lead compound optimization for SARS-CoV-2 main protease (M) and Cyclin-dependent Kinase 2 (CDK2), respectively. The selected lead optimization molecules are synthesized and evaluated for their in-vitro activities against CDK2, displaying improved CDK2 activity.
基于结构的生成化学在计算机辅助药物发现中至关重要,它可以探索广阔的化学空间,设计与靶标具有高结合亲和力的配体。然而,传统的计算方法受到计算效率的限制,而机器学习方法由于自回归采样而面临瓶颈。为了解决这些问题,我们开发了一种条件深度生成模型 PMDM,用于根据指定的靶标生成 3D 分子。PMDM 由具有局部和全局分子动力学的条件等变扩散模型组成,使 PMDM 能够考虑条件化的蛋白质信息,从而有效地生成分子。全面的实验表明,PMDM 在多个评估指标上均优于基准模型。为了评估 PMDM 在实际药物设计场景下的应用,我们分别针对严重急性呼吸系统综合征冠状病毒 2 主蛋白酶(M)和细胞周期蛋白依赖性激酶 2(CDK2)进行先导化合物优化。选择的先导优化分子进行了合成,并评估了它们对 CDK2 的体外活性,显示出改善的 CDK2 活性。
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