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| Amedeo Caflisch, University of Zurich |
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| Amedeo Caflisch (born in Italy in 1963) studied theoretical physics at the ETH in Zurich where he graduated in 1991. From 1992 until 1994 he was a postdoctoral fellow in the research group of Martin Karplus at the Chemistry Department of Harvard University. In 1996 he was appointed Assistant Professor and in 2001 Full Professor of Computational Structural Biology at the Institute of Biochemistry of the University of Zurich. His main research interests include structure-based drug design and molecular dynamics simulations of protein folding and aggregation. His research group develops software tools for docking and ligand design and currently applies the programs to beta-secretase (Alzheimer's disease) and kinases (cancer). The group belongs also to the CHARMM development team.
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Discovery of cell-permeable nonpeptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatic calculations
Danzhi Huang (1), Urs Luethi (2), Peter Kolb (1), Karin Edler (1,2), Marco Cecchini (1), Stephan Audetat (1,2), Alcide Barberis (2), and Amedeo Caflisch (1)
Affiliation:
(1) Department of Biochemistry, University of Zurich, Winterthurerstrasse 190
CH-8057 Zurich, Switzerland
(2) ESBATech AG, Wagistrasse 21, CH-8952 Zurich-Schlieren, Switzerland
A fragment-based docking procedure followed by substructure search was used to identify active-site beta-secretase inhibitors from a composite set of about 300,000 and a library of nearly 180,000 small molecules, respectively. After docking the compounds were ranked according to the binding affinity evaluated with a linear interaction energy approach with continuum electrostatics (LIECE). Values of EC_50 lower than 10 micromolar were measured in at least one of two different mammalian cell-based assays for 12 of the 72 purchased compounds. In particular, a phenylureathiadiazole derivative (MW=322 g/mol) and a diphenylureaderivative (MW=419 g/mol) are very promising lead compounds for beta-secretase inhibition to treat Alzheimer's disease. It is important to note that for almost all of the 12 compounds, for which an EC_50 value could be measured, the discrepancies between the LIECE predicted affinity and the experimental value is within the accuracy of the LIECE approach of about 1 kcal/mol.
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