Structure‐Based Drug Design Strategies for Inhibition of Aspartic Proteinases

Cooper, J.B.

doi:10.1002/9783527630943.ch4

Cited by 1 publication

(2 citation statements)

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“…As one of the transition state mimics, hydroxyethylenes evolved from statines designed for the aspartyl proteases renin and HIV1 protease. , The first disclosed HE 1 (OM99-2) was designed against BACE1 exhibiting a K i of 0.0016 μM. Its crystal structure (PDB code ), the first BACE1/inhibitor complex to be published, showed the key interaction between the hydroxyl functional group and the catalytic aspartates .…”

Section: Bace1 Inhibitor Designmentioning

confidence: 99%

“…A class of transition state mimics that were designed to successfully inhibit renin and HIV1 protease was adapted to design inhibitors for the closed form of BACE1. ,, Introduction of a basic amine to strengthen the interaction with the negatively charged catalytic aspartates in the hydroxyethylene series led to improved binding efficiency and potency with reduced shift in the cell potency. The design of HEAs also led to decreased MW and fewer amide linkages.…”

Section: Bace1 Inhibitor Designmentioning

confidence: 99%

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Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

Yuan¹,

Shankar²,

Zheng³

et al. 2013

J. Med. Chem.

129

134

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The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-β (Aβ) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aβ hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.

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Section: Bace1 Inhibitor Designmentioning

confidence: 99%