Background: The substrate sites of enzymes are attractive targets for structure-based inhibitor design. Two difficulties hinder efforts to discover and elaborate new (nonsubstrate-like) inhibitors for these sites. First, novel inhibitors often bind at nonsubstrate sites. Second, a novel scaffold introduces chemistry that is frequently unfamiliar, making synthetic elaboration challenging, Results: In an effort to discover and elaborate a novel scaffold for a substrate site, we combined structure-based screening with in-parallel synthetic elaboration. These techniques were used to find new inhibitors that bound to the folate site of Lactobacillus casei thymidylate synthase (LcTS), an enzyme that is a potential target for proliferative diseases, and is highly studied, The available chemicals directory was screened, using a molecular-docking computer program, for molecules that complemented the three-dimensional structure of this site. Five high-ranking compounds were selected for testing. Activity and docking studies led to a derivative of one of these, dansyltyrosine (K-i 65 mu M). Using solid-phase in-parallel techniques 33 derivatives of this lead were synthesized and tested. These analogs are dissimilar to the substrate but bind competitively with it. The most active analog had a K-i of 1.3 mu M. The tighter binding inhibitors were also the most specific for LcTS versus related enzymes, Conclusions: TS can recognize inhibitors that are dissimilar to, but that bind competitively with, the folate substrate. Combining structure-based discovery with in-parallel synthetic techniques allowed the rapid elaboration of this series of compounds. More automated versions of this approach can be envisaged.
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|Anno di pubblicazione:||1999|
|Titolo:||Structure-based discovery and in-parallel optimization of novel competitive inhibitors of thymidylate synthase|
|Autori:||D. Tondi; U. Slomczynska; MR Costi; DM Watterson; S. Ghelli; BK Shoichet|
|Autori interni:||TONDI, Donatella |
COSTI, Maria Paola
|Rivista:||CHEMISTRY & BIOLOGY|
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