Exploring the therapeutic potential of prolinamides as multi-targeted agents for Alzheimer's disease treatment:
Samuel O Olalekan1, Vincent A Obakachi2, Abosede A Badeji3
1Department of Physiology, Olabisi Onabanjo University, Sagamu Campus, Sagamu, Ogun State Nigeria.
Abstract:
Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence expected to rise sharply in the coming years. Despite extensive research, effective treatments addressing the multifaceted pathophysiology of AD remain elusive. This study investigates the therapeutic potential of twenty-seven prolinamides (P1 - P27), with the focus on their interactions with key proteins implicated in AD pathogenesis. Four of the compounds, namely; 10-((4-nitrophenyl)prolyl)-10 H-phenothiazine (P14), 2-((4-nitrophenyl)prolyl)isoindoline (P19), 1-(4-formylphenyl)-N-(p-tolyl)pyrrolidine-2-carboxamide (P22), and N,1-bis(4-nitrophenyl)pyrrolidine-2-carboxamide (P27) showed promising potential as Alzheimer's drug. In-silico approaches including molecular docking, molecular dynamic (MD) simulation, post md study, physicochemical and drug-likeness parameters were employed to ascertain the potential of these compounds as inhibitors of certain proteins implicated in the pathophysiology of Alzheimer's disease. Molecular docking and dynamics simulations demonstrated that P14, P19, P22 and P27 exhibited promising binding affinities towards crucial AD-associated proteins, including Beta-Secretase 1 (BACE1), Butyrylcholinesterase (BuChE), and Tau-tubulin kinase 2 (TTBK2). Structural stability analyses revealed that prolinamides, particularly P22 and P27 for BACE1 and P14 and P19 for BuChE, exhibited greater stability than their reference ligands, indicated by lower RMSD, RoG, and RMSF values. For BuChE, Rivastigmine had a docking score of -7.0 kcal/mol, a binding free energy (ΔGbind) of -22.19 ± 2.44 kcal/mol, RMSD of 1.361 ± 0.162 Å, RMSF of 9.357 ± 3.212 Å, and RoG of 22.919 ± 0.064 Å, whereas P19 exhibited a superior docking score of -10.3 kcal/mol, a significantly better ΔGbind of -33.74 ± 2.84 kcal/mol, RMSD of 1.347 ± 0.132 Å, RMSF of 8.164 ± 2.748 Å, and RoG of 22.868 ± 0.070 Å. Physicochemical and pharmacokinetic assessments affirmed the drug-likeness and bioavailability of P19 notably capable of penetrating the blood-brain barrier. Compounds P19 and P22, emerged as multi-targeted ligands, offering the potential for simultaneous modulation of multiple AD-related pathways. These findings highlight the possibilities of these compounds to be explored as novel therapeutic agents for AD. They also highlight the need for further experimental validation to confirm their efficacy and safety profiles, advancing them toward clinical application in AD management.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s40203-024-00250-z.
Insights
New prolinamides show promise as Alzheimer's disease (AD) treatments. Compounds P19 and P22 demonstrated multi-targeted inhibition of key AD proteins, suggesting potential for novel therapeutic strategies.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Computational Drug Discovery
Background:
- Alzheimer's disease (AD) is a growing global health concern with limited effective treatments.
- The complex pathophysiology of AD necessitates novel therapeutic approaches targeting key proteins.
Purpose of the Study:
- To investigate the therapeutic potential of twenty-seven prolinamides as inhibitors of AD-associated proteins.
- To identify lead compounds with favorable binding affinities, stability, and drug-likeness for AD treatment.
Main Methods:
- In-silico methods including molecular docking, molecular dynamics (MD) simulations, and post-MD analyses.
- Assessment of physicochemical and pharmacokinetic properties, including blood-brain barrier penetration.
- Evaluation of binding affinities and structural stability against AD-related targets like BACE1, BuChE, and TTBK2.
Main Results:
- Four prolinamides (P14, P19, P22, P27) showed significant binding affinities to BACE1, BuChE, and TTBK2.
- P19 demonstrated superior binding affinity and stability for BuChE compared to Rivastigmine.
- P19 and P22 exhibited multi-targeted inhibition and favorable drug-likeness, with P19 showing good blood-brain barrier penetration potential.
Conclusions:
- Selected prolinamides, particularly P19 and P22, represent promising candidates for novel Alzheimer's disease therapeutics.
- These compounds offer potential for multi-targeted modulation of AD pathways.
- Further experimental validation is crucial to confirm efficacy and safety for clinical application.
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