Novel allosteric covalent inhibitors of bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa identified by virtual screening

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Ruiz, Victor¹  Czyzyk, Daniel J.¹  Valhondo, Margarita²  Jorgensen, William L.²  Anderson, Karen S.^1,3 

[1] Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 USA

[2] Yale Univ, Dept Chem, 225 Prospect St,POB 208107, New Haven, CT 06520 USA

[3] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, 333 Cedar St, New Haven, CT 06520 USA

关键词: Cryptosporidium hominis;    DHFR;    Non-active site;    Allosteric;    Virtual screen;    Glide;   

DOI  :  10.1016/j.bmcl.2019.03.022

来源: Elsevier

【 摘 要 】

Protozoans of the genus Cryptosporidium are the causative agent of the gastrointestinal disease, cryptosporidiosis, which can be fatal in immunocompromised individuals. Cryptosporidium hominis (C. hominis) bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in the folate biosynthesis pathway and a molecular target for inhibitor design. Previous studies have demonstrated the importance of the ChTS-DHFR linker region crossover helix to the enzymatic activity and stability of the ChDHFR domain. We conducted a virtual screen of a novel non-active site pocket located at the interface of the ChDHFR domain and crossover helix. From this screen we have identified and characterized a noncompetitive inhibitor, compound 15, a substituted diphenyl thiourea. Through subsequent structure activity relationship studies, we have identified a time-dependent inhibitor lead, compound 15D17, a thiol-substituted 2-hydroxy-N-phenylbenzamide, which is selective for ChTS-DHFR, and whose effects appear to be mediated by covalent bond formation with a non-catalytic cysteine residue adjacent to the non-active site pocket.

【 授权许可】

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