|"Protein structure-based drug design is rapidly gaining momentum. The new opportunities, developments and results in this field are almost unbelievable ..."|
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descriptions of research
Dr. Verlinde studied pharmacy at the University of Leuven in Belgium when these studies were chemically oriented. He then joined the lab of professor Camiel De Ranter at the University of Leuven, Belgium. In 1988 he obtained his Ph.D. with as thesis K-opioids in the 6,7-benzomorphan series: x-ray crystallography, conformational analysis and pharmacophore modelling. In 1989 he joined the group of professor Wim Hol at the University of Groningen, The Netherlands, to learn protein crystallography and structure-based drug design. In 1992 he moved to the University of Washington as a post-doc, and in 1995 he became a research assistant professor at the same university. Now he is an associate professor of biochemistry.
Research in the Verlinde group is in the field of structure-based drug design, based on the Drug Design Cycle.
Some of our early work focused on the optimization of adenosine, a 50 mM ligand, to design a potent inhibitor of trypanosomal glyceraldehyde-3-phosphate dehydrogenase with as structural input the complex of the enzyme with NAD. With the structure of the mammalian enzyme in hand we included selectivity as a design criterion. These efforts resulted in a 200 nM enzyme inhibitor that blocks trypanosomal glycolysis and growth in culture at low µM concentrations; no significant inhibition of the mammalian enzyme was seen. Subsequently, we explored the adenosine scaffold further in a focused library design study using the DOCK program. We examined two fusion positions on the scaffold, one with an amine library consisting of approximately 460 amines, and another position with a carboxylic acid library consisting of approximately 1400 acids. Of the virtual 644,000 compounds we selected 240 compounds for synthesis, resulting in 40 additional compounds that inhibit parasite GAPDH in the low µ range.
We also designed a macrocyclic inhibitor of peptide deformylase using the FLO/QXP software. The idea behind the design was to reduce conformational freedom compared to a linear compound. The cyclic inhibitor showed potent inhibitory activity toward E. coli deformylase (Ki = 0.67 nM) and antibacterial activity against both Gram-positive and Gram-negative bacteria (MIC = 0.7-12 µg/mL).
In 2004 Dr. Fan and Dr. Verlinde collaborated to design a compound by linking two different ligands. It is hetero-bivalent ligand of cholera toxin and serum amyloid-P component that promotes the hetero-dimerization of the two pentamer proteins.
Dr. Verlinde was also engaged within the framework of MMV (Medicines for Malaria Venture) in a collaboration with Drs. Van Voorhis, Buckner and Gelb (UW Dept. of Chemistry) where the goal was to design focused libraries of tetrahydroquinoline inhibitors of P. falciparum protein farnesyltransferase to arrive at a new oral clinical candidate for malaria. In this project extensive use is made of the combinatorial library docking capabilities of the FLO/QXP software. He, Dr. Buckner and Dr. Gelb are also using structure-based methods to design T.cruzi CYP51 inhibitors for treating patients with Chagas disease.
In the last couple of years Dr. Verlinde has been working with Drs. Fan, Buckner and Hol on the inhibition of trypanosomal Methionyl-tRNA synthetases from various trypanosomes. Subnanomolar inhibitors have been created that cure mice.