Identification of a novel class of inhibitor of human and Escherichia coli thymidine phosphorylase by in silico screening

被引:20
作者
McNally, VA [1 ]
Gbaj, A [1 ]
Douglas, KT [1 ]
Stratford, IJ [1 ]
Jaffar, M [1 ]
Freeman, S [1 ]
Bryce, RA [1 ]
机构
[1] Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester M13 9PL, Lancs, England
基金
英国医学研究理事会;
关键词
D O I
10.1016/j.bmcl.2003.08.010
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 IC50 value of 20 muM and an IC50 value of 77 muM 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. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3705 / 3709
页数:5
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