Characterizing the Chemical Space of γ-Secretase Inhibitors and Modulators

Abstract

γ-Secretase (GS) is one of the most attractive molecular targets for the treatment of Alzheimer’s disease (AD). Its key role in the final step of amyloid-β peptides generation and its relationship in the cascade of events for disease development have caught the attention of many pharmaceutical groups. Over the past years, different inhibitors and modulators have been evaluated as promising therapeutics against AD. However, despite the great chemical diversity of the reported compounds, a global classification and visual representation of the chemical space for GS inhibitors and modulators remain unavailable. In the present work, we carried out a two-dimensional (2D) chemical space analysis from different classes and subclasses of GS inhibitors and modulators based on their structural similarity. Along with the novel structural information available for GS complexes, our analysis opens the possibility to identify compounds with high molecular similarity, critical to finding new chemical structures through the optimization of existing compounds and relating them with a potential binding site.

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

“…A challenge remains in accurately predicting the structures of peptide-like inhibitors, which may be overcome through using specialized peptide docking approaches [ 84 , 85 , 86 ], although there is evidently no difficulty in selecting such molecules by the screening approaches presented here. The virtual screening strategies presented here incorporate both ligand- and structure-based approaches, whereas these have been investigated individually in previous studies [ 87 , 88 ].…”

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

“…Tarenflurbil (R-flurbiprofen) was tested in a large phase-III trial, without success however (Green et al, 2009 ), likely because brain concentrations of the agent were insufficient to mediate a pharmacological effect (Karran and Hardy, 2014 ). In general, the first GSM generation lacked potency, and, besides some academic work (Saretz et al, 2021 ), this chemical space (Santiago et al, 2021 ; Mekala et al, 2020 ) has largely been abandoned.…”

“…Examples of the most potent compounds in these series are EVP-0015962 (Rogers et al, 2012 ), GSM2 (Kretner et al, 2011 ), and BIIB042 (Scannevin et al, 2016 ), all with EC 50 values for Aβ 42 lowering in the double-digit nM range. However, their drug-like properties were suboptimal and there are no reports of their effects in human studies (Mekala et al, 2020 ; Santiago et al, 2021 ).…”