The molecular pruning of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen

Lisa Y Wu; Marc O Anderson; Yoko Toriyabe; Jack Maung; Tammy Y Campbell; Cheryl Tajon; Marat Kazak; Jamie Moser; Clifford E Berkman

doi:10.1016/j.bmc.2007.07.028

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The molecular pruning of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen

Journal article

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The molecular pruning of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen

Lisa Y Wu, Marc O Anderson, Yoko Toriyabe, Jack Maung, Tammy Y Campbell, Cheryl Tajon, Marat Kazak, Jamie Moser and Clifford E Berkman

Bioorganic & medicinal chemistry, Vol.15(23), pp.7434-7443

12/01/2007

DOI: https://doi.org/10.1016/j.bmc.2007.07.028

Handle:

https://hdl.handle.net/2376/115075

PMCID: PMC2065856

PMID: 17869524

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https://doi.org/10.1016/j.bmc.2007.07.028View

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Abstract

Glutamate Carboxypeptidase II - antagonists & inhibitors

Amides - chemical synthesis

Stereoisomerism

Humans

Crystallography, X-Ray

Male

Structure-Activity Relationship

Zinc - chemistry

Computer Simulation

Drug Design

Molecular Structure

Binding Sites

Glutamate Carboxypeptidase II - chemistry

Oligopeptides - chemistry

Amides - pharmacology

Oligopeptides - chemical synthesis

Phosphoric Acids - chemical synthesis

Recombinant Proteins - antagonists & inhibitors

Phosphoric Acids - chemistry

Models, Molecular

Recombinant Proteins - chemistry

Antigens, Surface - chemistry

Phosphoric Acids - pharmacology

Small Molecule Libraries

Amides - chemistry

Organometallic Compounds - chemistry

Oligopeptides - pharmacology

To identify the pharmacophore of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen (PSMA), a small analog library was designed and screened for inhibitory potency against PSMA. The design of the lead inhibitor was based upon N-acyl derivatives of endogenous substrate folyl-gamma-Glu and incorporates a phosphoramidate group to interact with the PSMA catalytic zinc atoms. The scope of the analog library was designed to test the importance of various functional groups to the inhibitory potency of the lead phosphoramidate. The IC(50) for the lead phosphoramidate inhibitor was 35 nM while the IC(50) values for the analog library presented a range from 0.86 nM to 4.1 microM. Computational docking, utilizing a recently solved X-ray crystal structure of the recombinant protein, along with enzyme inhibition data, was used to propose a pharmacophore model for the PSMA active site.

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Title: The molecular pruning of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen
Creators: Lisa Y Wu - Department of Chemistry & Biochemistry, San Francisco State University, 1600 Holloway Avenue, San Francisco, CA 94132, USA
Marc O Anderson
Yoko Toriyabe
Jack Maung
Tammy Y Campbell
Cheryl Tajon
Marat Kazak
Jamie Moser
Clifford E Berkman
Publication Details: Bioorganic & medicinal chemistry, Vol.15(23), pp.7434-7443
Academic Unit: Chemistry, Department of
Publisher: England
Grant note: S06 GM052588 / NIGMS NIH HHS S06 GM052588-080022 / NIGMS NIH HHS R21 CA122126-01 / NCI NIH HHS S06-GM052588 / NIGMS NIH HHS
Identifiers: 99900548121101842
Language: English
Resource Type: Journal article