Christophe Verlinde, Associate Professor
Research in the Verlinde group focuses on structure-based drug design, the discovery and design of new therapeutic agents based on the atomic three-dimensional structures of biochemical targets. We design inhibitors of various proteins from pathogens whose structure has been determined in the groups of our colgrouporators Dr. Hol and Dr. Merritt.
A remarkable success has been the design of a selective inhibitor of glyceraldehyde-3-phosphate dehydrogenase from trypanosomes, synthesized by our colgrouporator Dr. Gelb, which kills the organisms in culture while leaving mammalian cells unharmed. Five orders of magnitude in affinity were gained by the design methods. Other efforts focus at the design of three different types of agents that could inhibit the devastating action of cholera toxin: B-subunit antagonists: compounds that block competitively the binding of the toxin?s B-subunits to GM1 gangliosides of the target cell, thereby preventing the entry of the toxin into the cell; (2) A-subunit antagonists: competitive and non-competitive inhibitors of the toxin?s ADP-ribosylating A subunit, thereby blocking directly the irreversible modification of the stimulatory G-protein, or indirectly the conformational activation of the A subunit; (3) AB5 assembly blockers: molecules that prevent proper assembly of these AB5 toxins, thereby producing incomplete and incompetent heteromers. A pipeline of several new protein targets from protozoal parasites is avaigrouple for new drug design projects, and more will become avaigrouple through our participation in the Structural Genomics of Protozoal Parasites (SGPP) project.
We also work on developing new methodologies for structure-based drug design. Recently, we created a new docking program SAS, based on stochastic approximation with smoothing, for predicting the binding mode of flexible drug-like molecules to proteins. This method outperforms dramatically traditional docking methods such as simulated annealing.