About: Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn(2+) to inhibit cysteinyl cathepsins: review and implications

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About: Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn(2+) to inhibit cysteinyl cathepsins: review and implications Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn(2+) to inhibit cysteinyl cathepsins: review and implications
Creator	Lockwood, T Lockwood, Thomas
Source	PMC
abstract	ABSTRACT: Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases; however, therapeutic inhibition has been problematic. Zn(2+) is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa) triads. Biguanide forms bidentate metal complexes through the two imino nitrogens. Here, it is discussed that phenformin (phenylethyl biguanide) is a model for recruitment of endogenous Zn(2+) to inhibit CysHis/CysHis(X) peptidolysis. Phenformin is a Zn(2+)-interactive, anti-proteolytic agent in bioassay of living tissue. Benzoyl-l-arginine amide (BAA) is a classical substrate of papain-like proteases; the amide bond is scissile. In this review, the structures of BAA and the phenformin-Zn(2+) complex were compared in silico. Their chemistry and dimensions are discussed in light of the active sites of papain-like proteases. The phenyl moieties of both structures bind to the “S2” substrate-binding site that is typical of many proteases. When the phenyl moiety of BAA binds to S2, then the scissile amide bond is directed to the position of the thiolate-imidazolium ion pair, and is then hydrolyzed. However, when the phenyl moiety of phenformin binds to S2, then the coordinated Zn(2+) is directed to the identical position; and catalysis is inhibited. Phenformin stabilizes a “Zn(2+) sandwich” between the drug and protease active site. Hundreds of biguanide derivatives have been synthesized at the 1 and 5 nitrogen positions; many more are conceivable. Various substituent moieties can register with various arrays of substrate-binding sites so as to align coordinated Zn(2+) with catalytic partners of diverse proteases. Biguanide is identified here as a modifiable pharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range of potencies and specificities. GRAPHICAL ABSTRACT: Phenformin-Zn(2+) Complex [Image: see text]
has issue date	2019-05-01(xsd:dateTime)
bibo:doi	10.1007/s10534-019-00197-1
bibo:pmid	31044334
has license	cc-by
sha1sum (hex)	b453be7df859d451667f709fbb0c843cf0b9f25c
schema:url	https://doi.org/10.1007/s10534-019-00197-1
resource representing a document's title	Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn(2+) to inhibit cysteinyl cathepsins: review and implications
has PubMed Central identifier	PMC6647370
has PubMed identifier	31044334
schema:publication	Biometals
resource representing a document's body	covid:b453be7df859d451667f709fbb0c843cf0b9f25c#body_text
is schema:about of	named entity 'IS A' named entity 'RECRUITMENT' named entity 'CATHEPSINS' named entity 'METAL COMPLEXES' named entity 'THEIR' named entity 'PROGRESS' named entity 'INHIBITION' named entity 'ENDOGENOUS' named entity 'BIND' named entity 'ACTIVITIES' named entity 'CONTRIBUTE ' named entity 'EXCESSIVE' named entity 'DYADS' named entity 'AMIDE' named entity 'LIGHT' named entity 'RECRUITMENT' named entity 'SUBSTRATE' named entity 'THERAPEUTIC' named entity 'BENZOYL' named entity 'PROBLEMATIC' named entity 'CHEMISTRY' named entity 'REVIEW' named entity 'IMINO' named entity 'SUB-' named entity 'PHARMACOPHORE' named entity 'TO INHIBIT' named entity 'CYSTEINYL' named entity 'INTERACTIVE' named entity 'MODEL' named entity 'PROTEOLYTIC' named entity 'AMIDE BOND' named entity 'CATHEPSINS' named entity 'FORMS' named entity 'PEPTIDOLYSIS' named entity 'BIOASSAY' named entity 'PROTEASES' named entity 'DIMENSIONS' named entity 'TRIADS' named entity 'CLASSICAL' named entity 'BIDENTATE' named entity 'PHENFORMIN' named entity 'COMPARED' named entity 'PAPAIN' named entity 'HERE' named entity 'LIKE' named entity 'IN SILICO' named entity 'CYSTEINYL' named entity 'AGENT' named entity 'NATURAL' named entity 'LIVING TISSUE' named entity 'PHENYL' named entity 'IS A' named entity 'BIGUANIDE' named entity 'INHIBITOR' named entity 'TO INHIBIT' named entity 'ENDOGENOUS' named entity 'COMPLEX' named entity 'STRUCTURES' named entity 'REVIEW' named entity 'DISEASES' named entity 'ACTIVE SITES' named entity 'BIGUANIDE' named entity 'papain' named entity 'phenformin' named entity 'living tissue' named entity 'Biguanide' named entity 'Phenformin' named entity 'cysteinyl' named entity 'metal complexes' named entity 'bioassay' named entity 'Biguanide' named entity 'cysteinyl' named entity 'cysteinyl' named entity 'substrate' named entity 'substrates' named entity 'cathepsins' named entity 'selective affinity' named entity 'vanadium' named entity 'lysosomal degradation' named entity 'electronegativity'

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