title: Identification of a novel class of inhibitor of human and Escherichia coli thymidine phosphorylase by in silico screening.
abstract: Structure-based computational screening of the National Cancer Institute database of anticancer compounds identified novel non-nucleobase-derived inhibitors of human thymidine phosphorylase as candidates for lead optimization. The hierarchical in silico screening strategy predicted potentially strong low molecular weight ligands exhibiting a range of molecular scaffolds. Of the thirteen ligands assayed for activity, all displayed inhibitory activity against Escherichia coli thymidine phosphorylase. One compound, hydrazine carboxamide 2-[(1-methyl-2,5-dioxo-4-pentyl-4-imidazolidinyl)methylene], was found to inhibit E. coli thymidine phosphorylase with an IC(50) value of 20 microM and an IC(50) value of 77 microM against human thymidine phosphorylase. As this hydantoin derivative lacks the undesirable ionic sites of existing tight-binding nucleobase-derived inhibitors, such as 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]uracil hydrochloride, it provides an opportunity for the design of potent thymidine phosphorylase inhibitors with improved pharmacokinetic properties.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: V A
authors.initials: VA
authors.lastname: McNally
authors.forename: A
authors.initials: A
authors.lastname: Gbaj
authors.forename: K T
authors.initials: KT
authors.lastname: Douglas
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: M
authors.initials: M
authors.lastname: Jaffar
authors.forename: S
authors.initials: S
authors.lastname: Freeman
authors.forename: R A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D030541:Databases, Genetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006834:Hydrazines; D007093:Imidazoles; D011994:Recombinant Proteins; C486821:hydrazine carboxamide 2-((1-methyl-2,5-dioxo-4-pentyl-4-imidazolidinyl)methylene); D013939:Thymidine Phosphorylase; D013936:Thymidine