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| Xavier Barril obtained a Ph. D. from the University of Barcelona in 2001, where he studied a number of aspects of molecular recognition in the group of Professors F. Javier Luque and Modesto Orozco. For the last four years he has worked as Senior Scientist at Vernalis (Cambridge, UK), where he has been involved in different oncology projects, ranging all the way from target validation to pre-clinical stages. Most noticeably, his work on Hsp90 has contributed to the discovery and optimization of drug candidates. He has co-authored some 20 research papers as well as a number of reviews, book chapters and patents. Recently he has been appointed ICREA Research Professor at the Faculty of Pharmacy, Barcelona University, where he will study several aspects of Structure-Based Drug Discovery (SBDD). He is particularly interested in the improvement of current computational SBDD methods and its integration with a wider range of experimental technologies.
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The Issue of Protein Flexibility in Docking-Based Virtual Screening
Dr. Xavier Barril, ICREA and Departament de Fisicoquimica, Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
The binding sites of pharmacological targets tend to present a high degree of plasticity, which can range from relatively small ligand-induced fit effects to major changes in the shape and molecular recognition properties of a cavity. In pharmaceutical research, this can be exploited to identify classes of inhibitors with different interaction patterns and, potentially, very different overall properties. Nevertheless, for practical, computational and theoretical reasons, docking-based virtual screening (VS) generally uses only one conformation of the receptor. Although this should be a major limitation of the method, we have recently shown that using multiple X-ray structures in VS applications is likely to lead to worse results than standard rigid-receptor docking (J. Med. Chem., 48:4432, 2005). Here we will use the Hsp90 case to discuss which and how many cavities should be selected to attain optimal VS results, both in terms of enrichment factors and chemical diversity. The use of the consensus cavity scoring method will also be discussed.
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