3. The Human Pocketome

  1. Gisbert Schneider
  1. Ruben Abagyan1 and
  2. Clarisse Gravina Ricci1,2

Published Online: 11 OCT 2013

DOI: 10.1002/9783527677016.ch3

De novo Molecular Design

De novo Molecular Design

How to Cite

Abagyan, R. and Ricci, C. G. (2013) The Human Pocketome, in De novo Molecular Design (ed G. Schneider), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi: 10.1002/9783527677016.ch3

Editor Information

  1. ETH Zürich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland

Author Information

  1. 1

    University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, La Jolla, CA 92093, USA

  2. 2

    State University of Campinas–UNICAMP, Institute of Chemistry, Cx. P. 6154, Campinas, São Paulo, 13083–970, Brazil

Publication History

  1. Published Online: 11 OCT 2013
  2. Published Print: 13 NOV 2013

ISBN Information

Print ISBN: 9783527334612

Online ISBN: 9783527677016

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Keywords:

  • protein–protein interfaces;
  • ligand-binding cavities;
  • activity-specific subpockets;
  • PPARγ;
  • GPCR;
  • ligand docking

Summary

Small molecules of a living tissue, such as substrates, metabolites, xenobiotics, drugs, and environmental chemicals, bind transiently to the binding pockets on the surfaces of proteins or molecular assemblies. These binding surfaces can be roughly divided into (i) bigger flatter interfaces (predominantly protein–protein interfaces) and (ii) better shaped distinct cavities, fully or partially closed and sized for a smaller molecule, or its protruding part of around 25 ± 15 heavy atoms. These well-formed cavities are required for a high affinity complex with a double-digit nanomolar dissociation constant (Kd) observed for most target-specific drugs. We will define the latter type of the binding surfaces as “pockets,” and, in this chapter, we will analyze the emerging “structural pocketome” of a human cell in terms of its shape and content, geometrical variability and induced fit, and chemical selectivity. Finally, we will show how the three-dimensional conformational ensembles of particular pockets with or without cocrystallized binding partners can be converted to powerful methods for (i) screening chemicals for binding to a particular pocket or deorphanizing the activity of a chemical by screening it against the human pocketome, (ii) improving pocket docking predictions, and (iii) identifying activity-specific subpockets within the major binding pocket.