Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2- d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 1; pp. 107 - 110
• Main Authors: Price, MelissaL.P., Guida, WayneC, Jackson, TaraE, Nydick, JasonA, Gladstone, PatriciaL, Juarez, JoséC., Doñate, Fernando, Ternansky, RobertJ
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06.01.2003; Elsevier
• Subjects: Antineoplastic agents; Binding Sites; Biological and medical sciences; Computer Simulation; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Guanidines - chemistry; Guanidines - pharmacology; Humans; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structural Homology, Protein; Thymidine Phosphorylase - antagonists & inhibitors; Sulfur nitrogen heterocycle; Enzyme; Transferases; Glycosyltransferases; Enzyme inhibitor; Homology; Guanidines; In vitro; Modeling; Biological activity; Molecular model; Bicyclic compound; Chemical synthesis; Pentosyltransferases; Thymidine phosphorylase; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00828-4

A novel class of thymidine phosphorylase (TP) inhibitors has been designed based on analogy to the enzyme substrate as well as known inhibitors. Flexible docking studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2- d]pyrimidin-7-yl)-guanidines as well as their synthetic precursors provide insight into the observed experimental trends in binding affinity. A novel class of thymidine phosphorylase (TP) inhibitors has been designed based on analogy to the enzyme substrate as well as known inhibitors. Flexible docking studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2- d]pyrimidin-7-yl)-guanidines as well as their synthetic precursors provide insight into the observed experimental trends in binding affinity.