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Swiss Society for Crystallography - Howard Flack Crystallographic Lectures Series

Online Archiv

15. November 2021

Online via Zoom

Invited Talk

Fragment-based drug design  


Speaker: Prof. Amedeo Caflisch, University of Zurich

Host: Prof. Dr. Antonia Neels, Head of the Center for X-ray Analytics, Empa



We have developed a program for the docking of libraries of fragments (molecules with a molecular weight smaller than 300 g/mol) that makes use of a force field energy-evaluation with an implicit model of the solvent[1]. By means of high-throughput docking we have identified small-molecule inhibitors of six human bromodomains, protein modules that bind acetylated histone tails. In the case of the CREBBP bromodomain, optimization of the initial hits by chemical synthesis of derivatives has resulted in several low-nanomolar binders with favorable ligand efficiency and high selectivity against other bromodomains[2]. Thus, the screening of fragment libraries by docking is very efficient (24,000 molecules in a day on a commodity desktop) and the hit rate, i.e., the number of active molecules among the purchased compounds, is very high (typically 10% to 30%). We have validated the predicted binding modes by solving the crystal structure of about 150 bromodomain/ligand complexes. Two lead compounds for the CREBBP bromodomain and the Ephrin tyrosine kinases, respectively, have shown antiproliferative activity in mouse xenograft models[3,4].


[1] Chem. Inf. Model., 60, 10, 4881–4893 (2020)

[2] ACS Cent. Sci., 4, 2, 180–188 (2018)

[3] RSC Med. Chem., 11, 665-675 (2020)

[4] Eur. J. Med. Chem., 112 (2016) 347-366 (2016)



About the Speaker 





Amedeo Caflisch studied Theoretical Physics at the Swiss Federal Institute of Technology in Zurich where he graduated in 1991. From 1992 until 1994 he was a postdoctoral fellow in the research group of Prof. Martin Karplus at the Department of Chemistry of Harvard University. Caflisch joined the Department of Biochemistry of the University of Zurich in 1995 as a senior research assistant and was appointed assistant professor in 1996. In 2001 he was promoted to Full Professor of Computational Structural Biology at the Department of Biochemistry.


The activities of his research group include the development and application of computational methods to investigate protein folding and aggregation, as well as structure-based drug design.