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Enzyme mechanisms and inhibition

One of the main motivations for studying transition states and enzyme mechanisms is to design better enzyme inhibitors as drugs. Over 300 drugs in current use are enzyme inhibitors, including anti-cancer, anti-hypertension drugs, and anti-HIV drugs, and many antibiotics. The influenza drugs oseltamivir and zanamivir are transition state mimics that were designed based on transition state structures derived from KIEs.

Antibiotic resistance

Antibiotic resistance is a major problem. In Canada, some types of antibiotic resistance are increasing 10-fold per decade. Around the world, tuberculosis killed 1.7 million people in 2009, and rates of extensively drug-resistant tuberculosis (XDR-TB) are increasing rapidly. It is almost 100% fatal within 3 weeks. In this context, it is troubling that only two new classes of antibiotics have been introduced in the last 40 years.

α-Carboxyketose synthases

CKS reactionWe have developed potent inhibitors against bacterial α-carboxyketose synthases. They are essential for bacterial virulence (DAHP synthase) or survival (KDO8P synthase, NeuB), and are therefore attractive broad-spectrum antibiotic targets.

The original inhibitors in this class, oxime-based molecules, are potent competitive inhibitors with nM to pM Ki values. They are mimics (through the nitrogen lone pair and bridging water molecules) of the tetrahedral intermediates formed in the reaction.


xtal_closeupThese inhibitors have some good characteristics (very high affinity, long residence times in the active site), and some undesirable ones (slow binding to some proteins, not binding to all the active sites in the tetrameric protein). We have performed mutagenesis studies, determined multiple crystal structures, are studying protein dynamics by hydrogen-deuterium exchange (in collaboration with Derek Wilson's lab at York University), and are performing protein NMR studies to understand inhibition works, and how binding information from one active site is transmitted tens of Ångstroms to the neighbouring active sites.

tetramer inhibWe are continuing our inhibitor developement in several directions — exploring the binding affinity of related inhibitors, using fragment-based inhibitor design (wiki) to explore new functional groups, and searching for mimics of the transition state of intermediate formation, which could be even more potent inibitors of these antibiotic targets.

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