Chemogenomics pp 249-279 | Cite as

The Flexible Pocketome Engine for Structural Chemogenomics

  • Ruben Abagyan
  • Irina Kufareva
Part of the Methods in Molecular Biology book series (MIMB, volume 575)


Biological metabolites, substrates, cofactors, chemical probes, and drugs bind to flexible pockets in multiple biological macromolecules to exert their biological effect. The rapid growth of the structural databases and sequence data, including SNPs and disease-related genome modifications, complemented by the new cutting-edge 3D docking, scoring, and profiling methods has created a unique opportunity to develop a comprehensive structural map of interactions between any small molecule and biopolymers. Here we demonstrate that a comprehensive structural genomics engine can be built using multiple pocket conformations, experimentally determined or generated with a variety of modeling methods, and new efficient ensemble docking algorithms. In contrast to traditional ligand-activity-based engines trained on known chemical structures and their activities, the structural pocketome and docking engine will allow prediction of poses and activities for new, previously unknown, protein binding sites, and new, previously uncharacterized, chemical scaffolds. This de novo structure-based activity prediction engine may dramatically accelerate the discovery of potent and specific therapeutics with reduced side effects.

Key words

Pocketome Chemical biology Flexible docking Ensemble docking Drug screening Activity prediction SCARE algorithm Binding site Virtual ligand screening 



The authors would like to thank Giovanni Bottegoni, Maxim Totrov, Jianghong An, Seva Katritch, Sojung Park, Anton Cheltsov, William Bisson, George Nicola, and Manuel Rueda for their help, discussions, images, and creative contributions into the methods reported and described in this chapter. This work was partially funded by NIH/NIGMS grants 5-R01-GM071872-02 and 1-R01-GM074832-01A1.


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Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Ruben Abagyan
    • 1
  • Irina Kufareva
    • 1
  1. 1.Department of Molecular BiologyThe Scripps Research InstituteLa JollaUSA

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