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 nomanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed.
Structure-based studies on species-specific inhibition of thymidylate synthase / Costi, Maria Paola; Tondi, Donatella; Rinaldi, Marcella; Barlocco, Daniela; Pecorari, Piergiorgio; Soragni, Fabrizia; Venturelli, Alberto; Stroud, Rm. - In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE. - ISSN 0925-4439. - STAMPA. - 1587:2-3(2002), pp. 206-214. [10.1016/S0925-4439(02)00083-2]
Structure-based studies on species-specific inhibition of thymidylate synthase
COSTI, Maria Paola;TONDI, Donatella;RINALDI, Marcella;BARLOCCO, Daniela;PECORARI, Piergiorgio;SORAGNI, Fabrizia;VENTURELLI, Alberto;
2002
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 nomanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed.Pubblicazioni consigliate
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