A Molecular Dynamics Ensemble-Based Approach for the Mapping of Druggable Binding Sites

Part of the Methods in Molecular Biology book series (MIMB, volume 819)


An expanding repertoire of “allosteric” drugs is revealing that structure-based drug design (SBDD) is not restricted to the “active site” of the target protein. Such compounds have been shown to bind distant regions of the protein topography, potentially providing higher levels of target specificity, reduced toxicity and access to new regions of chemical space. Unfortunately, the location of such allosteric pockets is not obvious in the absence of a bound crystal structure and the ability to predict their presence would be useful in the discovery of novel therapies. Here, we describe a method for the prediction of “druggable” binding sites that takes protein flexibility into account through the use of molecular dynamics (MD) simulation. By using a dynamic representation of the target, we are able to sample multiple protein conformations that may expose new drug-binding surfaces. We perform a fragment-based mapping analysis of individual structures in the MD ensemble using the FTMAP algorithm and then rank the most prolific probe-binding protein residues to determine potential “hot-spots” for further examination. This approach has recently been applied to a pair of human G-protein-coupled receptors (GPCRs), resulting in the detection of five potential allosteric sites.

Key words

Allosteric Molecular dynamics simulation Docking Binding site Drug design 



This work has been supported in part by the National Science Foundation (NSF), the National Institutes of Health (NIH), the Howard Hughes Medical Institute (HHMI), the National Biomedical Computation Resource (NBCR), the Center for Theoretical Biological Physics (CTBP), San Diego Supercomputer Center (SDSC), and the NSF Supercomputer Centers.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Chemistry and Biochemistry, Center for Theoretical Biological PhysicsUniversity of California, San DiegoLa JollaUSA
  2. 2.Howard Hughes Medical Institute, Departments of Chemistry and Biochemistry and Pharmacology, Center for Theoretical Biological PhysicsUniversity of California, San DiegoLa JollaUSA

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