Discovery of 4,4'-Dipyridylsulfide Analogs as "Switchable Electrophiles" for Covalent Inhibition

Electrophilic heterocycles offer attractive features as covalent fragments for inhibitor and probe development. A focused library of heterocycles for which protonation can enhance reactivity (called "switchable electrophiles") is screened for inhibition of the proposed drug target dimethylarginine dimethylaminohydrolase (DDAH). Several novel covalent fragments are identified: 4-chloroquinoline, 4-bromopyridazine, and 4,4-dipyridylsulfide. Mechanistic studies of DDAH inactivation by 4,4-dipyridylsulfide reveal selective covalent S-pyridinylation of the active-site Cys through catalysis by a neighboring Asp residue. Inactivation (kinact/KI = 0.33 M-1 s-1) proceeds with release of 4-thiopyridone (0.78 equiv), and structure-activity relationships reveal that the leaving group pKa can be modulated to tune reactivity. The use of a "switchable electrophile" strategy helps impart selectivity, even to fragment-sized modifiers. Identification of 4,4-dipyridylsulfide analogs as inactivators offers an easily tunable covalent fragment with multiple derivatization sites on both the leaving and staying groups.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:16

Enthalten in:

ACS chemical biology - 16(2021), 2 vom: 19. Feb., Seite 264-269

Sprache:

Englisch

Beteiligte Personen:

Ahn, Yeong-Chan [VerfasserIn]
May, Valerie K [VerfasserIn]
Bedford, Guy C [VerfasserIn]
Tuley, Alfred A [VerfasserIn]
Fast, Walter [VerfasserIn]

Links:

Volltext

Themen:

Amidohydrolases
Dimethylargininase
EC 3.5.-
EC 3.5.3.18
Enzyme Inhibitors
Journal Article
Pyridines
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Small Molecule Libraries
Sulfides

Anmerkungen:

Date Completed 28.06.2021

Date Revised 28.06.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1021/acschembio.0c00890

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM320542041