This section highlights my current research in ‘target-based drug discovery’ at UIC within the Institute of Tuberculosis Research at UIC (Department of Pharmaceutical Sciences).
After my postdoctoral training at Purdue University (1979-1985) with Prof. M. G. Rossmann as a macromolecular crystallographer (e.g. proteins and viruses), I was hired by Abbott Laboratories to setup the protein crystallography laboratory and use the X-ray crystallography methodology to support ‘Structure-Based Drug Design’ (SBDD). I worked at Abbott for over twenty-two years doing SBDD for various targets. The concept and methodology of target-based and structure-based drug design is outlined in Figs. 1a, b.
The protein of interest is crystallized possibly in the presence of a ligand (A, e. g. inhibitor) bound and the structure determined by X-ray crystallography. Analysis of the bound ligand A (i.e. molecular modeling) permits the study the inter-molecular interactions between the target and the ligand, from which a hypothetical superior compound B is designed, synthesized and characterized. Ligand B is also crystallized bound to the enzyme and the process is repeated. After several cycles, an optimized compound can be considered for further development, possibly leading to a drug candidate.
Projects at the Institute for Tuberculosis Research
Currently, this methodology is being used at the ITR to identify, validate and optimize compounds for two targets of interest for anti-TB therapy:
- ClpC1: Important target for protein homeostasis. This target is essential for the survival of the M. tuberculosis pathogen. The structures of two potent natural macro-cyclic peptides Rufomycin and Ecumicin bound to the N-terminal domain of ClpC1 (i.e. ClpC1-NTD) have been characterized. Fig. 2a,b.
- FBPasesII: Key enzyme in the gluconeogenesis pathway of many organisms. This is an exploratory target. Fig.3. View of the active site with the key elements for catalysis color coded: PO4-6 binding, Arg165-Pro166-Arg167 (cyan); substrate F1,6BP binding, Asp187-Gly188-Asp189 (green); Helical N-term, PO4-1 binding site Thr89xxxLys94 (blue); and metal Mn2+ binding site, Asp84—Glu87 (dark grey). Substrate Fructose-1,6-bisphosphate (green).
For further information look for publications within this website. Consult also my official website within the Pharmaceutical Sciences website (https://pharmacy.uic.edu/profiles/caz/).