Allosteric modulation plays a critical role in enzyme functionality and requires a deep understanding of the interactions between the active and allosteric sites. γ-Secretase (GS) is a key therapeutic target in the treatment of Alzheimer's disease (AD), through its role in the synthesis of amyloid β peptides that accumulate in AD patients. This study explores the structure and dynamic effects of GS modulation by E2012 binding, employing well-tempered metadynamics and conventional molecular dynamics simulations across three binding scenarios: (1) GS enzyme with and without L458 inhibitor, (2) the GS-substrate complex together with the modulator E2012 in two different binding modes, and (3) E2012 interacting with a C99 substrate fragment. Our findings reveal that the presence of L458 induces conformational changes that contribute to stabilization of the GS enzyme dynamics, previously reported as a key factor that allowed the resolution of the cryo-EM structure and the enhanced binding of E2012. Furthermore, we identified the most favorable binding site for E2012 within the GS-substrate complex, uncovering significant modulatory effects and a complex network of interactions that influence the position of the substrate for catalysis. In addition, we explore a potential substrate-modulator binding before the formation of the enzyme-substrate complex. The insights gained from our study emphasize the importance of these interactions in the development of potential therapeutic interventions that target the functionality of the GS enzyme in AD.

01 Jan 2024·Current Topics in Medicinal Chemistry

Gamma Secretase as an Important Drug Target for Management of Alzheimer’s Disease: A Comprehensive Review

Review

Author: Hakem, Fady Tadros ; Arafa, Reem K ; Fouad, Youstina Farid

Abstract:Alzheimer’s disease (AD) is a neurological disease that affects the memory. AD has been attributed to the aggregations of amyloid-β (Aβ) peptides which result in the formation of plaques that block the neuron-transferring process done by the brain memory cells. These plaques are formed upon cleavage of Amyloid Precursor Protein (APP) by Gamma-Secretase (GS). GS protein has around 141 substrates, the important two are APP and Notch. Considering one of the hot spots in AD research, we focused on GS and its relation to AD. Moreover, a lot of research was done on beta-secretase and drugs were developed to target it however, few drugs are established for GS. GS contains four subunits: Presenilin (PS), PEN-2, Nicastrin, and APH-1. The catalytic subunit is PS, which contains the active site for substrate binding, as well as the allosteric and docking sites. Both PEN-2 and APH-1 are regulators for the stability and activity of GS. Nicastrin, helps the substrates bind to the PS. Additionally, the role of the immuno-protein named “IFITM3” and how it affects the immune system and its relation to AD is presented. GS is one of the most studied proteins with many developed candidates as inhibitors (GSI) and modulators (GSM). Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted.

01 Jan 2021·CellQ1 · BIOLOGY

Structural basis of γ-secretase inhibition and modulation by small molecule drugs

Q1 · BIOLOGY

Article

Author: Yigong Shi ; Xuefei Guo ; Rui Zhou ; Chuangye Yan ; Guanghui Yang ; Jianlin Lei

Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the β strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors.

100 Deals associated with E-2012

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 1	US	Eisai Co., Ltd.	-

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