title: Binding cavities and druggability of intrinsically disordered proteins.
abstract: To assess the potential of intrinsically disordered proteins (IDPs) as drug design targets, we have analyzed the ligand-binding cavities of two datasets of IDPs (containing 37 and 16 entries, respectively) and compared their properties with those of conventional ordered (folded) proteins. IDPs were predicted to possess more binding cavity than ordered proteins at similar length, supporting the proposed advantage of IDPs economizing genome and protein resources. The cavity number has a wide distribution within each conformation ensemble for IDPs. The geometries of the cavities of IDPs differ from the cavities of ordered proteins, for example, the cavities of IDPs have larger surface areas and volumes, and are more likely to be composed of a single segment. The druggability of the cavities was examined, and the average druggable probability is estimated to be 9% for IDPs, which is almost twice that for ordered proteins (5%). Some IDPs with druggable cavities that are associated with diseases are listed. The optimism versus obstacles for drug design for IDPs is also briefly discussed.
authors.affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Center for Quantitative Biology, Peking University, Beijing, 100871, China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Huaiqing
authors.initials: H
authors.lastname: Cao
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Liu
mesh_terms: D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D064267:Intrinsically Disordered Proteins; D008024:Ligands
keywords: drug design; drug target; druggability; intrinsically disordered protein; ligandability; molecular recognition; pE-DB