Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer's treatment

Nasimudeen R Jabir; Md Tabish Rehman; Khadeejah Alsolami; Shazi Shakil; Torki A Zughaibi; Raed F Alserihi; Mohd Shahnawaz Khan; Mohamed F AlAjmi; Shams Tabrez

doi:10.1080/07853890.2021.2009124

Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer's treatment

Ann Med. 2021 Dec;53(1):2332-2344. doi: 10.1080/07853890.2021.2009124.

Authors

Nasimudeen R Jabir¹, Md Tabish Rehman², Khadeejah Alsolami³, Shazi Shakil^{4

5

6}, Torki A Zughaibi^{4

5}, Raed F Alserihi^{5

7}, Mohd Shahnawaz Khan⁸, Mohamed F AlAjmi², Shams Tabrez^{4

5}

Affiliations

¹ Department of Biochemistry, Centre for Research and Development, PRIST University, Thanjavur, India.
² Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
³ Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif, Saudi Arabia.
⁴ King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.
⁷ 3D Bioprinting Unit, Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁸ Department of Biochemistry, College of Sciences, King Saud University, Riyadh, Saudi Arabia.

Abstract

Introduction: Alzheimer's disease (AD), the most predominant cause of dementia, has evolved tremendously with an escalating frequency, mainly affecting the elderly population. An effective means of delaying, preventing, or treating AD is yet to be achieved. The failure rate of dementia drug trials has been relatively higher than in other disease-related clinical trials. Hence, multi-targeted therapeutic approaches are gaining attention in pharmacological developments.

Aims: As an extension of our earlier reports, we have performed docking and molecular dynamic (MD) simulation studies for the same 13 potential ligands against beta-site APP cleaving enzyme 1 (BACE-1) and γ-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and γ-secretase was performed using AutoDock enabled PyRx v-0.8. The protein-ligand interactions were analyzed in Discovery Studio 2020 (BIOVIA). The stability of the most promising ligand against BACE-1 and γ-secretase was evaluated by MD simulation using Desmond-2018 (Schrodinger, LLC, NY, USA).

Results: The computational screening revealed that the docking energy values for each of the ligands against both the target enzymes were in the range of -7.0 to -10.1 kcal/mol. Among the 13 ligands, 8 (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed binding energies of ≤-8 kcal/mol against BACE-1 and γ-secretase. For the selected enzyme targets, BACE-1 and γ-secretase, 6Z5 displayed the lowest binding energy of -10.1 and -9.8 kcal/mol, respectively. The MD simulation study confirmed the stability of BACE-6Z5 and γ-secretase-6Z5 complexes and highlighted the formation of a stable complex between 6Z5 and target enzymes.

Conclusion: The virtual screening, molecular docking, and molecular dynamics simulation studies revealed the potential of these multi-enzyme targeted ligands. Among the studied ligands, 6Z5 seems to have the best binding potential and forms a stable complex with BACE-1 and γ-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies.

Keywords: Alzheimer’s disease; drug development; enzyme targets; molecular docking; multi-targeted ligands.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease* / drug therapy
Amyloid Precursor Protein Secretases* / chemistry
Amyloid Precursor Protein Secretases* / metabolism
Humans
Ligands
Molecular Docking Simulation

Substances

Ligands
Amyloid Precursor Protein Secretases

Grants and funding

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number IFPIP: 1012-141-1442 and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.