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

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 gamma-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and gamma-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 gamma-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 gamma-secretase. For the selected enzyme targets, BACE-1 and gamma-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 gamma-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 gamma-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies.

Automated summary

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