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Identifying the binding mode of a molecular scaffold

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Abstract

We describe a method for docking of a scaffold-based series and present its advantages over docking of individual ligands, for determining the binding mode of a molecular scaffold in a binding site. The method has been applied to eight different scaffolds of protein kinase inhibitors (PKI). A single analog of each of these eight scaffolds was previously crystallized with different protein kinases. We have used FlexX to dock a set of molecules that share the same scaffold, rather than docking a single molecule. The main mode of binding is determined by the mode of binding of the largest cluster among the docked molecules that share a scaffold. Clustering is based on our `nearest single neighbor' method [J. Chem. Inf. Comput. Sci., 43 (2003) 208–217]. Additional criteria are applied in those cases in which more than one significant binding mode is found. Using the proposed method, most of the crystallographic binding modes of these scaffolds were reconstructed. Alternative modes, that have not been detected yet by experiments, could also be identified. The method was applied to predict the binding mode of an additional molecular scaffold that was not yet reported and the predicted binding mode has been found to be very similar to experimental results for a closely related scaffold. We suggest that this approach be used as a virtual screening tool for scaffold-based design processes.

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Authors and Affiliations

  1. Department of Medicinal Chemistry and the David R. Bloom Center for Pharmacy, School of Pharmacy, Hebrew University of Jerusalem, 91120, Israel

    Doron Chema & Amiram Goldblum

  2. School of Chemistry, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel

    Doron Chema & Doron Eren

  3. ProChon Biotech Ltd., 2 Holzman St, Kiryat Weizmann, Rehovot, Israel

    Doron Chema & Avner Yayon

  4. Lilly Forschung GmbH, Essener Str. 93, D-22419, Hamburg, Germany

    Andrea Zaliani

Authors
  1. Doron Chema
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  2. Doron Eren
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  4. Amiram Goldblum
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  5. Andrea Zaliani
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Correspondence to Amiram Goldblum.

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Chema, D., Eren, D., Yayon, A. et al. Identifying the binding mode of a molecular scaffold. J Comput Aided Mol Des 18, 23–40 (2004). https://doi.org/10.1023/B:JCAM.0000022561.76694.5b

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