Details Matter in Structure-based Drug Design

SCS Senior Industrial Science Award 2022

Authors

  • Bernd Kuhn Roche Pharma Research and Early Development, Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
  • Jens-Uwe Peters Roche Pharma Research and Early Development, Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
  • Markus G. Rudolph Roche Pharma Research and Early Development, Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
  • Peter Mohr Roche Pharma Research and Early Development, Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
  • Martin Stahl Roche Pharma Research and Early Development, Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
  • Andreas Tosstorff Roche Pharma Research and Early Development, Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland

DOI:

https://doi.org/10.2533/chimia.2023.489

PMID:

38047790

Keywords:

Intramolecular hydrogen bond, Ligand strain, Molecular interactions, PDE10

Abstract

Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD. Data mining in crystal structure databases can help to identify these sometimes subtle effects, but it is also a great resource to learn about molecular recognition in general and can be used as part of molecular design tools. We illustrate the use of the Cambridge Structural Database for identifying preferred structural motifs for intramolecular hydrogen bonding and of the Protein Data Bank for deriving propensities for protein-ligand interactions.

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Published

2023-08-09

How to Cite

[1]
B. Kuhn, J.-U. Peters, M. G. Rudolph, P. Mohr, M. Stahl, A. Tosstorff, Chimia 2023, 77, 489, DOI: 10.2533/chimia.2023.489.