Discovery of γ-Secretase Modulators with a Novel Activity Profile by Text-Based Virtual Screening

Abstract

We present an integrated approach to identify and optimize a novel class of γ-secretase modulators (GSMs) with a unique pharmacological profile. Our strategy included (i) virtual screening through application of a recently developed protocol (PhAST), (ii) synthetic chemistry to discover structure-activity relationships, and (iii) detailed in vitro pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer's disease. They modulate the γ-secretase product spectrum (i.e., amyloid-β (Aβ) peptides of different length) and induce a shift from toxic Aβ42 to shorter Aβ species such as Aβ38 with no or minimal effect on the overall rate of γ-secretase cleavage. We describe the identification of a series of 4-hydroxypyridin-2-one derivatives, which display a novel type of γ-secretase modulation with equipotent inhibition of Aβ42 and Aβ38 peptide species.

Competitive Mirror Image Phage Display Derived Peptide Modulates Amyloid Beta Aggregation and Toxicity

“…Both concentrations of Mosd1 showed no signs of γ-secretase activity inhibition, i.e. the γ-secretase substrate APP CTFβ was not accumulated as it is the case for the treatment with the γ-secretase inhibitor DAPT ( Fig 11 ) [ 41 , 42 ].…”

Pharmacophore Alignment Search Tool (PhAST): Significance Assessment of Chemical Similarity

“…E ‐values and a significance cutoff could provide an important guideline to adjust this number to the circumstances of a specific screening. Furthermore, they would open up a complete new field of application for PhAST besides being a successful virtual screening tool:44,74,75 It could be used for the (off‐)target prediction that only recently was investigated with other approaches based on significance estimates 27…”

“…Graph canonicalization is performed by a combination of Minimum Volume Embedding (MVE) with connectivity equivalent to covalent bonds employing a Diffusion Kernel 71–73. In this study, we used a parameterization of PhAST that was established in prior studies:45,74,75 The affine gap penalty model was used with gap open penalty =−7 and gap extension penalty =−1. This combination yielded the highest screening performance in a previous study in combination with the not normalized alignment score as similarity measure 45.…”

Synthesis and Insecticidal Activity of Mesoionic Pyrido[1,2-α]pyrimidinone Derivatives Containing a Neonicotinoid Moiety

“…Intermediates A , B , and C were prepared according to the reported methods [ 38 , 39 , 40 , 41 , 42 , 43 ]. First, 2-chloro-5-chloromethylpyridine was slowly added to the aqueous solution of NaHCO 3 and 2-aminopyridine.…”