Doris Alexandra Schuetz, Thomas Seidel, Arthur Garon, Riccardo Martini, Markus Körbel, Gerhard F Ecker, Thierry Langer

In the absence of experimentally derived, three-dimensional structures of receptors in complex with active ligands, it is of high value to be able to gain knowledge about energetically favorable interaction sites solely from the structure of the receptor binding site. For de novo ligand design as well as for lead optimization, this information retrieved from the protein is inevitable. The herein presented method called GRAIL combines the advantages of traditional grid based approaches for the identification of interaction sites and the power of the pharmacophore concept. A reduced pharmacophoric abstraction of the target system enables the computation of all relevant interaction grid maps in short amounts of time. This allows to extend the utility of a grid based method for the analysis of large amounts of coordinate sets obtained by long-time MD simulations. In this way it is possible to assess conformation dependent characteristics of key interactions over time. Furthermore, conformational changes of the protein can be taken into account easily and information thus obtained well guide a rational ligand design process. A study employing MD trajectories of the oncology target Heat shock protein 90, showcases how well our novel approach GRAIL performs for a set of different inhibitors bound to their target protein and how molecular features of the inhibitors are subject to optimization.

Department of Pharmaceutical Chemistry, Department of Biochemistry and Cell Biology
Journal of Chemical Theory and Computation
Publication date
Publication status
E-pub ahead of print
Peer reviewed
Austrian Fields of Science 2012
104004 Chemical biology
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