Identifying the binding mode of a molecular scaffold

Doron Chema, Doron Eren, Avner Yayon, Amiram Goldblum, Andrea Zaliani

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageAmerican English
Pages (from-to)23-40
Number of pages18
JournalJournal of Computer-Aided Molecular Design
Volume18
Issue number1
DOIs
StatePublished - Jan 2004

Bibliographical note

Funding Information:
A.G. thanks the Israel Science Foundation for supporting this research by grant no. 608/02, and the Ministry of Science and Technology for a strategic grant which supported this work in part. Prochon Biotech thanks the Ministry of Trade and Industry for a grant as part of the Pharmacologica Consortium.

Keywords

  • Binding mode
  • Clustering
  • Docking
  • Kinase inhibitors
  • Scaffolds

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