Molecular Docking Studies of Interaction Curcumin against Beta-secretase 1, Amyloid A4 Protein, Gamma-secretase and Glycogen Synthase Kinase-3β as Target Therapy for Alzheimer Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia. In several studies we reviewed, curcumin can inhibit formation, extension, and destabilization of Amyloid A4 protein. Aim: This study aims to prove the consistency of curcumin as a candidate therapy for Alzheimer's disease using in silico approach. Methods: Biomolecular experimental study was conducted using in silico method supported by protein database, Pymol, Discovery studio, and PyRx software. A comprehensive literature search was conducted to found the potential target for Alzheimer's disease. We found Beta-secretase 1, Amyloid A4 protein, Gamma-secretase, and Glycogen synthase kinase (GSK)-3β as a protein target. Pharmacokinetic analysis was conducted based on the Lipinski Rule of Five criteria on the Lipinski Rule of Five websites and using the PreADMET website. Results: From the pharmacokinetic analysis, curcumin had met all the Lipinski and PreADMET criteria. The HIA and plasma binding test results showed 94.4% and 88%, which represent a good pharmacokinetic and bioavailability profile as a drug. GSK-3β had the strongest binding affinity with curcumin as recorded as -8.3 kcal/mol compared with the other four protein targets in this analysis. Conclusion: The strongest binding affinity between curcumin and GSK-3β reveals the potential target protein for Alzheimer's Disease therapy. Those interactions represent the potential involvement in the pathogenesis of Alzheimer's Disease with a modification of the additional sites on the tau molecule. This drug candidate discovery shows a preferable pharmacokinetics and bioavailability substance profile with a promising target through the Structure-based Drug Design (SBDD) approach. However, curcumin ability for BBB penetration still needs to be modified to improve its pharmacokinetic properties for becoming a novel Alzheimer's disease drug.