Structure of a eukaryotic thiaminase I.

Thiaminases, enzymes that cleave vitamin B1, are sporadically distributed among prokaryotes and eukaryotes. Thiaminase I enzymes catalyze the elimination of the thiazole ring moiety from thiamin through substitution of the methylene group with a nitrogenous base or sulfhydryl compound. In eukaryotic organisms, these enzymes are reported to have much higher molecular weights than their bacterial counterparts.

Focus on success: using a probabilistic approach to achieve an optimal balance of compound properties in drug discovery.

The success of any drug will depend on how closely it achieves an ideal combination of potency, selectivity, pharmacokinetics and safety. The key to achieving this success efficiently is to consider the overall balance of molecular properties of compounds against the ideal profile for the therapeutic indication from the earliest stages of a drug discovery project. The use of in silico predictive models of absorption, distribution, metabolism and elimination (ADME) and physicochemical properties is a major aid in this exercise, as it enables virtual molecules to be assessed across a broad range of properties from initial library generation, through to candidate selection.

Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate.

3-Deazathiamin diphosphate (deazaTPP) and a second thiamin diphosphate (TPP) analogue having a benzene ring in place of the thiazolium ring have been synthesised. These compounds are both extremely potent inhibitors of pyruvate decarboxylase from Zymomonas mobilis; binding is competitive with TPP and is essentially irreversible even though no covalent linkage is formed. DeazaTPP binds approximately seven-fold faster than TPP and at least 25,000-fold more tightly (K(i) less than 14 pM).