Cytosolic Glycerol-3-phosphate dehydrogenase 1 (GPD1, EC 1.1.1.8) plays a pivotal role in regulating the Embden-Meyerhof glucose glycolysis pathway (E-M pathway), as well as in conditions such as Huntington’s disease, cancer, and its potential role as a specific marker for Dormant Glioma Stem Cells. In this study, we conducted virtual screening using the ZINC database (http://zinc.docking.org/) and the GPD1 structure to identify potential GPD1 modulators. The investigation involved screening active candidate ligands using ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters, combined with molecular docking, pose analysis, and interaction analysis based on Lipinski and Veber criteria. Subsequently, the top 10 ligands were subjected to 200 ns all-atom molecular dynamics (M.D.) simulations, and binding free energies were calculated. The findings revealed that specific residues, namely TRP14, PRO94, LYS120, ASN151, THR264, ASP260, and GLN298, played a crucial role in ensuring system stability. Furthermore, through a comprehensive analysis involving molecular docking, molecular M.D., and DeLA-Drug, we identified 10 promising small molecules. These molecules represent potential lead compounds for developing effective therapeutics targeting GPD1-associated diseases, thereby contributing to a deeper understanding of GPD1-associated mechanisms. This study's significance lies in identifying key residues associated with GPD1 and discovering valuable small molecules, providing a foundation for further research and development.

胞质甘油-3-磷酸脱氢酶 1（GPD1，EC 1.1.1.8）在调节 Embden-Meyerhof 葡萄糖糖酵解途径（EM 途径）以及亨廷顿病、癌症等疾病中发挥着关键作用，及其潜在作用作为休眠神经胶质瘤干细胞的特异性标记。在本研究中，我们使用 ZINC 数据库 (http://zinc.docking.org/) 和 GPD1 结构进行虚拟筛选，以识别潜在的 GPD1 调节剂。该研究涉及使用 ADMET（吸收、分布、代谢、排泄、毒性）参数筛选活性候选配体，并结合基于 Lipinski 和 Veber 标准的分子对接、位姿分析和相互作用分析。随后，对前10个配体进行200 ns全原子分子动力学（MD）模拟，并计算结合自由能。研究结果表明，特定残基，即TRP14、PRO94、LYS120、ASN151、THR264、ASP260和GLN298，在确保系统稳定性方面发挥着至关重要的作用。此外，通过分子对接、分子MD和DeLA-Drug等综合分析，我们确定了10个有前途的小分子。这些分子代表了开发针对 GPD1 相关疾病的有效疗法的潜在先导化合物，从而有助于更深入地了解 GPD1 相关机制。本研究的意义在于鉴定了GPD1相关的关键残基，发现了有价值的小分子，为进一步的研究和开发提供了基础。