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

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

doi:10.2174/156802609790102383

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

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