Dataset Information

γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease.

ABSTRACT:

Background

Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid β peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation.

Methods

We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds.

Results

Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation.

Conclusions

AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.

SUBMITTER: Trasvina-Arenas CH

PROVIDER: S-EPMC10838598 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease.

Trasviña-Arenas Carlos Humberto CH Ayala Medina Luis Alejandro LA Vique-Sánchez José Luis JL

Reports of biochemistry & molecular biology 20230701 2

<h4>Background</h4>Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid β peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors fo ...[more]

PMID: 38317814

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Project description:INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering A? production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP ?-site cleavage (equivalent to A?40), and Notch ?-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A? production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A? was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A? reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A? production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A? in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A? was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Project description:IntroductionAlzheimer'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.AimsAs 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).ResultsThe 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.ConclusionThe 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.

Dataset Information

γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease.

Background

Methods

Results

Conclusions

Publications

γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease.

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