| Structure-based drug design,
the discovery and design of new therapeutic agents based on
the atomic three-dimensional structures of biochemical targets, is one
of the most rewarding but also the most challenging fields of biological
research.
My research focuses on solving three key problems to forge structure-based
drug design into a powerful method that will create the drugs of the 21st
century.
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Scoring functions: New methods are developed to predict fast but
accurately the affinity of ligands for a target protein, i.e. of the order
of 100,000 ligands in a week.
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Search methods: New ways are explored to exploit in computro
the flexibility of ligands and proteins in order to increase the odds of
finding a good match between them.
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Molecular pharmaco-kinetics and -dynamics: The current expertise
on chemical stability, drug metabolism and toxicity will get incorporated
in design strategies so that tightly binding inhibitors can be turned more
easily into drugs.
The unique multi-disciplinary environment of the Biomolecular Structure
Center not only ensures that this endeavor can succeed but also provides
ample of opportunities to apply structure-based drug design methods on
in-house projects. For this purpose, a battery of computer programs has
been brought in gear which encompasses visualization software, state-of-the-art
pharmacophore search programs, force-fields, docking programs, and de
novo design software. Ammunition is provided from no less than three
3D-databases of with each over one-hundred thousand potential ligands.
Thus far, significant progress has been achieved in the design of anti-trypanosomal
compounds. Efforts are underway to arrive at prophylactic drugs
for cholera and related diseases. |