title: Novel non-active site inhibitor of Cryptosporidium hominis TS-DHFR identified by a virtual screen.
abstract: The essential enzyme thymidylate synthase-dihydrofolate reductase (TS-DHFR) is a validated drug target for many pathogens, but has been elusive in Cryptosporidium hominis, as active site inhibitors of the enzymes from related parasitic protozoa show decreased potency and lack of species specificity over the human enzymes. As a rational approach to discover novel inhibitors, we conducted a virtual screen of a non-active site pocket in the DHFR linker region. From this screen, we have identified and characterized a noncompetitive inhibitor, flavin mononucleotide (FMN), with micromolar potency that is selective for ChTS-DHFR versus the human enzymes. These results describe a novel allosteric pocket amenable to inhibitor targeting, and a lead compound with which to move towards potent, selective inhibitors of ChTS-DHFR.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: W Edward
authors.initials: WE
authors.lastname: Martucci
authors.forename: Marina
authors.initials: M
authors.lastname: Udier-Blagovic
authors.forename: Chloe
authors.initials: C
authors.lastname: Atreya
authors.forename: Oladapo
authors.initials: O
authors.lastname: Babatunde
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Vargo
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D000495:Allosteric Site; D000818:Animals; D020134:Catalytic Domain; D003458:Cryptosporidium / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008958:Models, Molecular; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase