Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease

Title:Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease

Volume: 24 Issue: 19

Author(s): Saurabh G. Londhe, Mangala Shenoy, Suvarna G. Kini, Vinayak Walhekar and Dileep Kumar*

Affiliation:

• Department of Pharmaceutical Chemistry, BVDU’s Poona College of Pharmacy, Pune, 411038, Maharashtra, India
• Department of Entomology, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA
• UC Davis Comprehensive Cancer Centre, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA

Abstract:

Background: Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3β (GSK-3β) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it.

Objectives: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3β and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3β and AChE.

Methods: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger.

Results: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3β and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3β and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules.

Conclusion: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3β and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.

Cite this article as:

Londhe G. Saurabh, Shenoy Mangala, Kini G. Suvarna, Walhekar Vinayak and Kumar Dileep*, Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease, Current Topics in Medicinal Chemistry 2024; 24 (19) . https://dx.doi.org/10.2174/0115680266295740240602122613