title: Structure-based studies on species-specific inhibition of thymidylate synthase.
abstract: Thymidylate synthase (TS) is a well-recognized target for anticancer chemotherapy. Due to its key role in the sole de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is an essential enzyme in all life forms. As such, it has been recently recognized as a valuable new target against infectious diseases. There is also a pressing need for new antimicrobial agents that are able to target strains that are drug resistant toward currently used drugs. In this context, species specificity is of crucial importance to distinguish between the invading microorganism and the human host, yet thymidylate synthase is among the most highly conserved enzymes. We combine structure-based drug design with rapid synthetic techniques and mutagenesis, in an iterative fashion, to develop novel antifolates that are not derived from the substrate and cofactor, and to understand the molecular basis for the observed species specificity. The role of structural and computational studies in the discovery of nonanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, Via G. Campi n. 183, 41100, Modena, Italy. costimp@unimo.it
authors.forename: M Paola
authors.initials: MP
authors.lastname: Costi
authors.forename: Donatella
authors.initials: D
authors.lastname: Tondi
authors.forename: Marcella
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Daniela
authors.initials: D
authors.lastname: Barlocco
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pecorari
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Soragni
authors.forename: Alberto
authors.initials: A
authors.lastname: Venturelli
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stroud
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007780:Lacticaseibacillus casei / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D013045:Species Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D013940:Thymidylate Synthase