2. Coping with Complexity in Molecular Design

  1. Gisbert Schneider
  1. Michael M. Hann and
  2. Andrew R. Leach

Published Online: 11 OCT 2013

DOI: 10.1002/9783527677016.ch2

De novo Molecular Design

De novo Molecular Design

How to Cite

Hann, M. M. and Leach, A. R. (2013) Coping with Complexity in Molecular Design, in De novo Molecular Design (ed G. Schneider), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi: 10.1002/9783527677016.ch2

Editor Information

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

Author Information

  1. Chemical Sciences, Molecular Discovery Research, GSK Medicines Research Centre, Stevenage SG1 2NY, UK

Publication History

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

ISBN Information

Print ISBN: 9783527334612

Online ISBN: 9783527677016



  • lipophilic interactions;
  • protein–ligand crystal structures;
  • nuclear magnetic resonance;
  • X-ray crystallography;
  • high-throughput screening;
  • QSAR


In this chapter, we explore several issues of complexity in molecular design, focusing initially on the complexity model that we introduced over 10 years ago, which explores the probability of useful interactions occurring with ligands and binding sites of differing complexity. We explore some extensions of the model, which include uniqueness of binding mode and sensitivity of detection. In addition, we review the promiscuity data that supports and challenges the model, concluding that the use of molecular weight as a complexity measure does not account for the promiscuity introduced by excessive lipophilicity. We explore the subject of molecular interactions from the perspective of Shannon entropy and how this may help to understand some of the issues associated with lipophilic interactions. We then address the issues associated with sampling of chemical space and the challenges of understanding and navigating the vastness of such spaces. The challenge of understanding the complexity of thermodynamic entropy and enthalpy is also discussed. Finally, we discuss the challenges of taking a reductionist approach to drug discovery and how the emergence of new behaviors as complexity is rebuilt is difficult to predict and hence prepare for in advance.