Affiliations: [a] Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| [b] Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| [c] Department of Biochemistry, College of Science, King Saud University, Saudi Arabia
| [d] Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Incheon, Korea
Correspondence:
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Correspondence to: Anas Shamsi, PhD, MRSB, Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates. E-mail: [email protected].
Abstract: Background: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. Objective:Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity. Methods: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. Results: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. Conclusions: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.
Keywords: Alzheimer’s disease, drug repurposing, human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2, small molecule inhibitors, virtual screening
