Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics

A multidisciplinary approach was used to identify and optimize a quinazolinedione-based ligand that would reduce the flexibility of the substrate-covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of the aromatic amino acids. A computer-aided fragment-based protocol (ALTA) was first employed to identify the aromatic fragments able to block the interface pocket that separates two neighbor enzyme subunits and is located at the active site entrance. Chemical modification of its non-aromatic moiety through an olefin cross metathesis and Seebach ́s self-reproduction of chirality synthetic principle allowed the development of a quinazolinedione derivative that disables the catalytic loop plasticity, which is essential for the enzyme catalytic cycle. Molecular dynamics simulation studies revealed that the ligand would force the catalytic loop into an inappropriate arrangement for catalysis by strong interactions with the catalytic tyrosine and by expelling the essential arginine out of the active site.