Abstract

Structure-Based Design of Inhibitors of the Biosynthesis of Aromatic Amino Acids – Opportunities for Drug Discovery

Concepción González-Bello, Professor, Universidad De Santiago De Compostela

Infectious diseases caused by the development of drug resistance have become one of the most important public health issues of the early 21st century. Despite the recognized need for new antibiotics, only two new classes of antibiotics have been brought to the market in the last three decades. Therefore, the discovery of novel drugs and therapies to treat antibiotic-resistant infections and, particularly of drugs with new mechanisms of action is needed. Our research group is studying the possible development of new antibiotics whose mode of action is based on the selective and effective inhibition of an essential route in bacteria that does not have any counterpart in human cells, the essential amino acids biosynthesis. The talk will be focused on the inhibition of type II dehydroquinase and shikimate kinase, which are essential enzymes in Mycobacterium tuberculosis and Helicobacter pylori. Based on the enzyme mechanism, dynamic simulations and structural studies and by creating favorable interactions with key residues in the enzymatic mechanism several potent inhibitors were designed and identified. The crystal structures of enzyme/inhibitors complexes reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. Our results on this project will be presented.