Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR

Lamar, Jason; Hu, Jinqiang; Bueno, Ana B.; Yang, Hsiu‐Chiung; Guo, Deqi; Copp, James D.; McGee, J; Gitter, Bruce D.; Timm, David E.; May, Patrick C.; McCarthy, James R.; Chen, Shuhui

doi:10.1016/j.bmcl.2003.09.084

Cited by 45 publications

(32 citation statements)

References 22 publications

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“…Indeed, many potent BACE1 inhibitors have already been shown to reduce Aβ levels both in vitro and in vivo. [21][22][23][24][25][26][27] In addition to the efforts to identify small molecule BACE1 inhibitors, potential regulation of BACE1 activity by cellular factors also has been explored. For instances, it has been demonstrated that BACE1 activity is regulated by the state of glycosylation, 28 composition of lipids in the membrane bilayer, 29 interactions with heparin sulfate 30 and recently described reticulon proteins.…”

Section: Introductionmentioning

confidence: 99%

Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Shi

et al. 2006

Journal of Molecular Biology

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Section: Introductionmentioning

confidence: 99%

Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Shi

et al. 2006

Journal of Molecular Biology

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“…3,16 Encouragingly, some recent inhibitors have been reported to show good activity in cell-based assays. 17,18 Despite these successes, there is still a need to identify less-peptidic BACE inhibitors with lower molecular mass that are suitable for oral delivery and transport through the blood brain barrier.…”

mentioning

confidence: 99%

Apo and Inhibitor Complex Structures of BACE (β-secretase)

Patel¹,

Vuillard²,

Cleasby³

et al. 2004

Journal of Molecular Biology

181

211

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“…The publication of the first two crystal structures with the HE group [12,13] led to a manifold of structure activity relationship studies (SAR) with this isostere [42][43][44][45][46]. Other motifs have also appeared in the literature, and some of them are variants of the statine and HE isosteres:…”

Section: Molecular Diversity and The Isostere Chemical Structurementioning

confidence: 97%

The Search for Drug Leads Targeted to the β -Secretase: An Example of the Roles of Computer Assisted Approaches in Drug Discovery

Villaverde

Gonzalez-Louro²,

Sussman

2007

CTMC

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The inhibition of beta-secretase has become a very promising approach to control the onset and progression of Alzheimer's disease due to its involvement in the generation of amyloid plaques. The main goal of the many drug discovery projects targeting this enzyme is the identification of highly specific, non-peptidic compounds with low molecular weight, characteristics that are desirable for drug leads with low toxicity that have to transverse the blood brain barrier. We describe the main approaches used in the discovery of novel inhibitors, including substrate specificity, target structure based design, and high throughput screening (HTS), both in vitro and in silico. We place special emphasis in the receptor based design and in silico HTS, two strategies that make wide use of computer assisted tools. To exemplify the usefulness and versatility of computer tools in this endeavor we use the computer generated 'enzyme's binding site cast' to rationalize qualitatively some salient structural features of known beta-secretase second generation inhibitors, and for guiding the review of many of the ligands whose complexes with the enzyme have been studied by X-ray crystallography. We discuss the use made by other authors of molecular modelling for the understanding of the very special characteristics of ligand binding to beta-secretase and for the design of new inhibitors. Finally, we review the quest for non-peptidic inhibitors that has led to the use of HTS in vitro and in silico. The screening of extensive libraries resulted in a few low affinity compounds that do not fit into the key S1/S1' pockets, indicating that this is not an easy target to block.

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Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR

Cited by 45 publications

References 22 publications

Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Apo and Inhibitor Complex Structures of BACE (β-secretase)

The Search for Drug Leads Targeted to the β -Secretase: An Example of the Roles of Computer Assisted Approaches in Drug Discovery

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Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR

Cited by 45 publications

References 22 publications

Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Mapping of Interaction Domains Mediating Binding between BACE1 and RTN/Nogo Proteins

Apo and Inhibitor Complex Structures of BACE (β-secretase)

The Search for Drug Leads Targeted to the &#946; -Secretase: An Example of the Roles of Computer Assisted Approaches in Drug Discovery

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Product

Resources

About

The Search for Drug Leads Targeted to the β -Secretase: An Example of the Roles of Computer Assisted Approaches in Drug Discovery