Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
Department of Biochemistry, Aligarh Muslim University, Aligarh, India.
J Alzheimers Dis. 2024;100(2):475-485. doi: 10.3233/JAD-240376.
HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) plays a pivotal role as a control enzyme in ketogenesis, and its association with the amyloid-β protein precursor (AβPP) in mitochondria implicates a potential involvement in Alzheimer's disease (AD) pathophysiology.
Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity.
Exploiting the power of drug repurposing in conjunction with virtual screening and molecular dynamic (MD) simulations against 'HMGCS2', we present new in-silico insight into structure-based drug repurposing.
The initial molecules were screened for their binding affinity to HMGCS2. Subsequent interaction analyses and extensive 300 ns MD simulations were conducted to explore the conformational dynamics and stability of HMGCS2 in complex with the screened molecules, particularly Penfluridol and Lurasidone.
The study revealed that HMGCS2 forms stable protein-ligand complexes with Penfluridol and Lurasidone. Our findings indicate that Penfluridol and Lurasidone competitively bind to HMGCS2 and warrant their further exploration as potential repurposed molecules for anti-Alzheimer's drug development.
HMGCS2（线粒体 3-羟-3-甲基戊二酰基辅酶 A 合酶 2）作为酮体生成的关键酶，其与线粒体中的淀粉样β蛋白前体（AβPP）的关联表明其可能参与阿尔茨海默病（AD）的病理生理学。
我们的研究旨在利用 DrugBank 数据库识别可抑制 HMGCS2 活性的再利用药物。
利用药物再利用的力量，结合虚拟筛选和针对“HMGCS2”的分子动力学（MD）模拟，我们提出了一种基于结构的药物再利用的新的计算见解。
对初始分子进行了筛选，以检测它们与 HMGCS2 的结合亲和力。随后进行了相互作用分析和长达 300ns 的 MD 模拟，以探索与筛选分子（特别是奋乃静和鲁拉西酮）结合的 HMGCS2 的构象动力学和稳定性。
该研究表明 HMGCS2 与奋乃静和鲁拉西酮形成稳定的蛋白-配体复合物。我们的发现表明奋乃静和鲁拉西酮竞争性地与 HMGCS2 结合，这表明它们有必要进一步探索作为抗阿尔茨海默病药物开发的潜在再利用分子。
