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 Alserihi, Mohd Shahnawaz Khan, Mohamed F. Alajmi, Shams Tabrez
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: 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: studies.