Essential considerations for using protein–ligand structures in drug discovery

Protein–ligand structures are the core data required for structure-based drug design (SBDD). Understanding the error present in this data is essential to the successful development of SBDD tools. Methods for assessing protein–ligand structure quality and a new set of identification criteria are presented here. When these criteria were applied to a set of 728 structures previously used to validate molecular docking software, only 17% were found to be acceptable. Structures were re-refined to maintain internal consistency in the comparison and assessment of the quality criteria. This process resulted in Iridium, a highly trustworthy protein–ligand structure database to be used for development and validation of structure-based design tools for drug discovery.

► Quality criteria for identification of reliable protein–ligand structures are presented. ► Electron density is essential for structure evaluation in structure-based drug design. ► High quality structure databases will address clerical errors–20% was observed. ► Iridium quality criteria applied to 728 structures – only 17% were high quality. ► All re-refined Iridium structures (highly, mildly and not trustworthy) are available.