Abstract
γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.
Highlights
Introduction γSecretase is an intramembrane aspartyl protease that performs regulated intramembrane proteolysis of Type-I transmembrane (TM) proteins [1], processing over 100 functionally diverse substrates [2,3]
Accurate structural predictions for γ-secretase modulators are only possible via the pharmacophorebased approach, with the best virtual screening performances being centered on the use of pharmacophore-derived poses and their subsequent refinement, rather than redocking with full ligand flexibility
The modulator site represents a type of site that is unlikely to be considered in the development of molecular docking and scoring approaches, which, in turn, may connote the use of pharmacophore-derived poses and further refinements to these in screening for modulators
Summary
Strategies for the Identification of γ-Secretase Inhibitors and Modulators. School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia. Due to its role in APP processing, γ-secretase has been investigated for the development of disease-modifying therapeutics for Alzheimer’s Disease (AD), amongst other γ-secretase related disorders [11] These molecules are classified as γ-secretase inhibitors (GSIs), which target the enzyme active site, and γ-secretase modulators (GSMs) that bind to an allosteric site [12,13]. Many first generation GSIs, including L-685,458, were peptidic transition state analogs that feature hydroxyethylene dipeptide isostere moieties, allowing them to bind to γ-secretase in a way that mimics the α-helical nature of the APP TM domain [18] These molecules lack Notch-sparing activity and have not been pursued for development as therapeutic agents [19]. Ing both γ-secretase inhibitors and modulators based on these approaches were developed and validated
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