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Identification of Adenosine Deaminase Inhibitors by Metal‐binding Pharmacophore Screening
Author(s) -
Adamek Rebecca N.,
Ludford Paul,
Duggan Stephanie M.,
Tor Yitzhak,
Cohen Seth M.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000271
Subject(s) - pharmacophore , adenosine deaminase , inosine , chemistry , small molecule , drug discovery , combinatorial chemistry , high throughput screening , enzyme , adenosine , biochemistry , computational biology , biology
Adenosine deaminase (ADA) is a human mononuclear Zn 2+ metalloenzyme that converts adenosine to inosine. ADA is a validated drug target for cancer, but there has been little recent work on the development of new therapeutics against this enzyme. The lack of new advancements can be partially attributed to an absence of suitable assays for high‐throughput screening (HTS) against ADA. To facilitate more rapid drug discovery efforts for this target, an in vitro assay was developed that utilizes the enzymatic conversion of a visibly emitting adenosine analogue to the corresponding fluorescent inosine analogue by ADA, which can be monitored via fluorescence intensity changes. Utilizing this assay, a library of ∼350 small molecules containing metal‐binding pharmacophores (MBPs) was screened in an HTS format to identify new inhibitor scaffolds against ADA. This approach yielded a new metal‐binding scaffold with a K i value of 26±1 μM.