Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators (original) (raw)
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Discovery of notch-sparing gamma-secretase inhibitors
Current Alzheimer research, 2010
Overwhelming evidence supports a central role for the amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Abeta from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting gamma-secretase, which generates the C-terminus of Abeta; however, gamma-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter gamma-secretase activity to reduce Abeta production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that gamma-secretase can be selectively inhibited in this way by naphthyl-substituted gamma-aminoketones and gamma-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing gamma-secretase inhibitor...
Background: Alzheimer's disease (AD) is a neurodegenerative disorder in elderly persons aged above 65 years. The cleavage of amyloid precursor protein (APP) by -secretase generates peptide fragment A42, the main cause of memory and cognitive defects in AD. Therefore, elevated level of -secretase results in accumulation of insoluble form of A peptides (senile plaques) representing the protein as an attractive drug target of AD. Methods: Five recently reported -secretase antagonist (thiazolidinediones, rosiglitazone, pioglitazone, SC7 and tartaric acid) structural analogs were searched from ligand info database and prepared using LigPrep. The crystal structure of -secretase was optimized using Maestro v9.2 protein preparation wizard applying optimized potential for liquid simulations (OPLS)-2005 force field. Structure based virtual screening was performed for -secretase from prepared ligands using virtual screening workflow of Maestro v9.2 and was ranked based on XP Gscore....
Uncovering the Binding Mode of γ-Secretase Inhibitors
2019
Knowledge of how transition state inhibitors bind to γ-secretase is of major importance for the design of new Alzheimer’s disease therapies. Based on the known structure of γ-secretase in complex with a fragment of the amyloid precursor protein we have generated a structural model of γ-secretase in complex with the effective L-685,458 transition state inhibitor. The predicted binding mode is in excellent agreement with experimental data, mimicking all enzyme-substrate interactions at the active site and forming the relevant transition state geometry with the active site aspartate residues. In addition, we found that the stability of the complex is very likely also sensitive to the pH value. Comparative simulations on the binding of L-685,458 and the epimer L682,679 allowed us to explain the strongly reduced affinity of the epimer for γ-secretase. The structural model could form a valuable basis for the design of new or modified γ-secretase inhibitors.
Journal of Clinical and Scientific Research
Background: Alzheimer's disease (AD) is a neurodegenerative disorder in elderly persons aged above 65 years. The cleavage of amyloid precursor protein (APP) by -secretase generates peptide fragment A42, the main cause of memory and cognitive defects in AD. Therefore, elevated level of -secretase results in accumulation of insoluble form of A peptides (senile plaques) representing the protein as an attractive drug target of AD. Methods: Five recently reported -secretase antagonist (thiazolidinediones, rosiglitazone, pioglitazone, SC7 and tartaric acid) structural analogs were searched from ligand info database and prepared using LigPrep. The crystal structure of -secretase was optimized using Maestro v9.2 protein preparation wizard applying optimized potential for liquid simulations (OPLS)-2005 force field. Structure based virtual screening was performed for -secretase from prepared ligands using virtual screening workflow of Maestro v9.2 and was ranked based on XP Gscore. Results: Eight lead molecules were identified to have better binding affinity (lower XP Gscore) compared to five existing -secretase antagonists and appear to have good pharmacological properties. Binding orientations of the lead molecules were in well agreement with existing inhibitors. Lead1 showed lowest XP Gscore (-10.72 Kcal/mol). Molecular dynamics (MD) simulations of -secretase-lead1 complex was stable in all trajectories. Conclusion: Lead1 is proposed as potent inhibitor of -secretase and thus could be considered for rational drug design against AD.
ACS Medicinal Chemistry Letters, 2010
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC 50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
Molecules, 2009
Selective lowering of amyloid-β levels with small-molecule γ-secretase inhibitors is a promising therapeutic approach for Alzheimer's disease. In this work, we developed a high throughput assay for screening of γ-secretase inhibitors with endogenous γ-secretase and a fluorogenic substrate. The IC 50 values of known γ-secretase inhibitors generated with this method were comparable with reported values obtained by other methods. The assay was optimized and applied to a small-scale screening of 1,280 compounds. The discovery of several new inhibitors warrants further investigation. This assay was also proven to be easily adopted to test compounds for drosophila and mouse γsecretase, which could be very useful to assess compounds activity against γ-secretase from different species before the in vivo test in animal models.
β-Secretase-1: In Silico Drug Reposition for Alzheimer’s Disease
International Journal of Molecular Sciences
The β-secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer’s disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer’s with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BA...
Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease
Expert Opinion on Drug Discovery, 2012
Introduction: In an attempt of altering the natural history of Alzheimer's disease (AD), several compounds have been developed with the aim of inhibiting g-secretase, the enzymatic complex generating b-amyloid (Ab) peptides (Ab 1-40 and Ab 1-42), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiological cascade of AD. Areas covered: This article briefly reviews the profile of g-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on g-secretase inhibitors published before November 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting b-amyloid, g-secretase inhibitors, dementia syndromes and Alzheimer's disease. Expert opinion: Studies in both transgenic and non-transgenic animal models of AD have indicated that g-secretase inhibitors, administered by the oral route, are able to lower brain Ab concentrations. However, scanty data are available on the effects of these compounds on brain Ab deposition after prolonged administration. g-Secretase inhibitors may cause significant toxicity in experimental animals and in humans believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective g-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.