论文标题
深度学习的应用和评估潜在的NMDA受体拮抗剂的生成
Application and Assessment of Deep Learning for the Generation of Potential NMDA Receptor Antagonists
论文作者
论文摘要
N-甲基D-天冬氨酸受体(NMDAR)的非竞争性拮抗剂在治疗神经系统疾病(如帕金森氏症和阿尔茨海默氏症)方面具有治疗益处,但有些也会引起分离作用,这些作用已导致非法药物的合成。因此,对于新的药物开发以及抢先和识别新的设计师药物,都需要在计算机中产生NMDAR拮抗剂的能力。最近,生成深度学习模型已应用于从头毒品设计,作为扩展可以探索潜在药物样化合物的化学空间量的一种手段。在这项研究中,我们评估了生成模型在NMDAR中实现两个主要目标的应用:(i)创建和释放实验验证的NMDAR Phencyclidine(PCP)现场拮抗剂,以帮助药物发现社区,以及(ii)对这种生成人工智能模型的限制和当前的限制限制了这两种优势。我们将用于标准药物发现分析中的各种配体和结构的评估技术应用于深度学习生成的化合物中的各种基于配体和结构的评估技术。我们提出了十二位候选拮抗剂,这些拮抗剂在现有的化学数据库中不可用,以提供此类工作流程可以实现的示例,尽管仍然需要对这些化合物的合成和实验验证。
Uncompetitive antagonists of the N-methyl D-aspartate receptor (NMDAR) have demonstrated therapeutic benefit in the treatment of neurological diseases such as Parkinson's and Alzheimer's, but some also cause dissociative effects that have led to the synthesis of illicit drugs. The ability to generate NMDAR antagonists in silico is therefore desirable both for new medication development and for preempting and identifying new designer drugs. Recently, generative deep learning models have been applied to de novo drug design as a means to expand the amount of chemical space that can be explored for potential drug-like compounds. In this study, we assess the application of a generative model to the NMDAR to achieve two primary objectives: (i) the creation and release of a comprehensive library of experimentally validated NMDAR phencyclidine (PCP) site antagonists to assist the drug discovery community and (ii) an analysis of both the advantages conferred by applying such generative artificial intelligence models to drug design and the current limitations of the approach. We apply, and provide source code for, a variety of ligand- and structure-based assessment techniques used in standard drug discovery analyses to the deep learning-generated compounds. We present twelve candidate antagonists that are not available in existing chemical databases to provide an example of what this type of workflow can achieve, though synthesis and experimental validation of these compounds is still required.