Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators

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.

Presenilin homologues influence substrate binding and processing by γ-secretase: a molecular simulation study

“…APP vs Notch vs other substrates, as different types of substrates are shown to affect γ-secretase conformation differently, which may be harnessed for future structural based drug design. 69 Notably, we observe different conformations between PS1-and PS2-γ-secretase bound to NEXT substrates, which implies that PS1-and PS2-complexes could be targeted differently. This is supported by PS1 vs PS2 selectivity that is already evident in γ-secretase-targeting small molecules that have been developed through traditional medicinal chemistry pipelines.…”

ADME profiling, molecular docking, DFT, and MEP analysis reveal cissamaline, cissamanine, and cissamdine from Cissampelos capensis L.f. as potential anti-Alzheimer's agents

“…Gamma-secretase (GS), an essential aspartyl protease embedded within the membrane, is known for its role in the selective cleavage of Type-I transmembrane (TM) proteins, influencing over a hundred distinct substrates with varying functions. 104 This enzyme complex, characterized by its heterotetrameric composition, includes the presenilin homologues PS1 and PS2, 105 nicastrin (Nct), 106 anterior pharynx defective-1 (Aph-1), 107 and presenilin enhancer-2 (Pen-2). 108 Key among its substrates is the Amyloid Precursor Protein (APP) 109 and the Notch receptors 1 to 4.…”

New precision medicine avenues to the prevention of Alzheimer’s disease from insights into the structure and function of γ-secretases

“…The availability of highly resolved γ-secretase structures (Fig. 3 ) (Yang et al, 2021 ) opens the path to computer modeling, in silico screening, and rational drug design approaches (Ioppolo et al, 2021 ). The binding site of the prototype imidazole-based GSAS E2012 (Yang et al, 2021 ; Cai et al, 2017 ) is at the interface between PSEN1 and NCSTN on the extracellular side of the complex and partially covers the substrate-binding tunnel (Fig.…”