Extraction of Protein Binding Pockets in Close Neighborhood of Bound Ligands Makes Comparisons Simple Due to Inherent Shape Similarity

• Published in: Journal of chemical information and modeling Vol. 54; no. 11; pp. 3229 - 3237
• Main Authors: Krotzky, Timo, Rickmeyer, Thomas, Fober, Thomas, Klebe, Gerhard
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24-11-2014
• Subjects: Binding Sites; Coenzymes - metabolism; Comparative analysis; Drug Discovery - methods; Ligands; Models, Molecular; Protein Binding; Protein Conformation; Proteins; Proteins - chemistry; Proteins - metabolism
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci500553a

Methods for comparing protein binding sites are frequently validated on data sets of pockets that were obtained simply by extracting the protein area next to the bound ligands. With this strategy, any unoccupied pocket will remain unconsidered. Furthermore, a large amount of ligand-biased intrinsic shape information is predefined, inclining the subsequent comparisons as rather trivial even in data sets that hardly contain redundancies in sequence information. In this study, we present the results of a very simplistic and shape-biased comparison approach, which stress that unrestricted cavity extraction is essential to enable unexpected cross-reactivity predictions among proteins and function annotations of orphan proteins.