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Delineation of the Molecular Mechanisms of Nucleoside Recognition by Cytidine Deaminase through Virtual Screening
Author(s) -
Costanzi Stefano,
Vilar Santiago,
Micozzi Daniela,
Carpi Francesco M.,
Ferino Giulio,
Vita Alberto,
Vincenzetti Silvia
Publication year - 2011
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.201100139
Subject(s) - cytidine deaminase , cytidine , chemistry , virtual screening , gemcitabine , docking (animal) , pyrimidine , steric effects , computational biology , enzyme , active site , stereochemistry , nucleoside , mechanism of action , rational design , lead compound , biochemistry , combinatorial chemistry , drug discovery , biology , medicine , genetics , nursing , chemotherapy , in vitro
Abstract Cytidine deaminase (EC 3.5.4.5, CDA), an enzyme of the pyrimidine salvage pathways, is responsible for the degradation and inactivation of several cytidine‐based antitumor drugs such as cytarabine, gemcitabine, decitabine, and azacytidine. Thus, CDA inhibitors are highly sought after as compounds to be co‐administered with said drugs to improve their effectiveness. Alternatively, the design of antitumor drugs not susceptible to the action of CDA is also regarded as an attractive solution. Herein we describe a virtual screen for CDA ligands based on chemical similarity and molecular docking. The campaign led to the identification of three novel inhibitors and one novel substrate, with a 19 % hit rate, and allowed a significant extension of the structure–activity relationships, also in light of the compounds that resulted inactive. The most active compound identified through the screen is the inhibitor pseudoisocytidine, which has the potential to serve as a lead for highly stable compounds. The study also delineated the detrimental effect of 5‐aza and 6‐aza substitutions, the incompatibility of the presence of an amino group at the 3′‐position, as well as the presence of very strict steric requirements around the 2′‐arabino position and, even more, the N4‐position. Importantly, these features can be exploited for the design of novel anti‐neoplastic agents resistant to the action of CDA.