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Front. Chem. | doi: 10.3389/fchem.2018.00068

How Diverse are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

  • 1Department of Informatics, University of Hamburg, Germany
  • 2Molécules thérapeutiques in silico (MTi), Paris Diderot University, France

Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set (“Sperrylite Dataset”) of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules—each represented by a minimum of ten structures—and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from

Keywords: bioactive conformational space, protein-bound ligand conformation, Conformational variability, PDB, protein-ligand interaction, Binding site, small-molecule drug, cofactor

Received: 16 Jan 2018; Accepted: 05 Mar 2018.

Edited by:

Daniela Schuster, Paracelsus Private Medical University of Salzburg, Austria

Reviewed by:

Francesco Ortuso, Magna Græcia University, Italy
Esther Kellenberger, Université de Strasbourg, France
Sereina Riniker, ETH Zürich, Switzerland  

Copyright: © 2018 Friedrich, Simsir and Kirchmair. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Johannes Kirchmair, University of Hamburg, Department of Informatics, Bundesstr. 43, Hamburg, 20146, Germany,