Abstract
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 4,548 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 http://www.zbh.uni-hamburg.de/sperrylite_dataset.
Highlights
The protein-bound (“bioactive”) conformations of ligands can differ substantially from those observed in solution, the gas phase and small-molecule crystal structures (Boström, 2001; Perola and Charifson, 2004; Seeliger and de Groot, 2010)
The Sperrylite Dataset is a collection of all high-quality X-ray structures of small molecules bound to biomacromolecules that are contained in the Protein Data Bank (PDB)
The Sperrylite Dataset presented in this work is a complete subset of high-quality conformations of protein-bound ligands extracted from the PDB
Summary
The protein-bound (“bioactive”) conformations of ligands can differ substantially from those observed in solution, the gas phase and small-molecule crystal structures (Boström, 2001; Perola and Charifson, 2004; Seeliger and de Groot, 2010). For the application of 3D computational approaches such as docking or de novo design methods in drug discovery, the protein-bound conformations of small molecules need to be known or at least determinable (Brameld et al, 2008). Diversity of Protein-Bound Conformations of Small Molecules. The Protein Data Bank (PDB) is the most comprehensive resource of experimental structural data on biomacromolecules and their interaction with small molecules (Berman et al, 2000). While the structural data available from the PDB are extremely valuable for the research of biomacromolecules and their interactions with small molecules, these data represent only a very small fraction of (known) interactions
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