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Fragment-Based Cocktail Crystallography by the Medical Structural Genomics of Pathogenic Protozoa Consortium

[ Vol. 9 , Issue. 18 ]

Author(s):

Christophe L.M.J. Verlinde, Erkang Fan, Sayaka Shibata, Zhongsheng Zhang, Zhihua Sun, Wei Deng, Jennifer Ross, Jessica Kim, Liren Xiao, Tracy L. Arakaki, Jurgen Bosch, Jonathan M. Caruthers, Eric T. Larson, Isolde LeTrong, Alberto Napuli, Angela Kelley, Natasha Mueller, Frank Zucker, Wesley C. Van Voorhis, Frederick S. Buckner, Ethan A. Merritt and Wim G.J. Hol   Pages 1678 - 1687 ( 10 )

Abstract:


The history of fragment-based drug discovery, with an emphasis on crystallographic methods, is sketched, illuminating various contributions, including our own, which preceded the industrial development of the method. Subsequently, the creation of the BMSC fragment cocktails library is described. The BMSC collection currently comprises 68 cocktails of 10 compounds that are shape-wise diverse. The utility of these cocktails for initiating lead discovery in structure-based drug design has been explored by soaking numerous protein crystals obtained by our MSGPP (Medical Structural Genomics of Pathogenic Protozoa) consortium. Details of the fragment selection and cocktail design procedures, as well as examples of the successes obtained are given. The BMSC Fragment Cocktail recipes are available free of charge and are in use in over 20 academic labs.

Keywords:

Structural genomics, drug design, malaria, trypanosomiasis, leishmaniasis, history

Affiliation:

Medical Structural Genomics of Pathogenic Protozoa (MSGPP), Biomolecular Structure Center (BMSC) and Department of Biochemistry, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.



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