title: Structural Isosteres of Phosphate Groups in the Protein Data Bank.
abstract: We developed a computational workflow to mine the Protein Data Bank for isosteric replacements that exist in different binding site environments but have not necessarily been identified and exploited in compound design. Taking phosphate groups as examples, the workflow was used to construct 157 data sets, each composed of a reference protein complexed with AMP, ADP, ATP, or pyrophosphate as well other ligands. Phosphate binding sites appear to have a high hydration content and large size, resulting in U-shaped bioactive conformations recurrently found across unrelated protein families. A total of 16 413 replacements were extracted, filtered for a significant structural overlap on phosphate groups, and sorted according to their SMILES codes. In addition to the classical isosteres of phosphate, such as carboxylate, sulfone, or sulfonamide, unexpected replacements that do not conserve charge or polarity, such as aryl, aliphatic, or positively charged groups, were found.
authors.forename: Yuezhou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratoire Molécules Thérapeutiques in silico (MTi), UMRS-973, Université Paris Diderot , Sorbonne Paris Cité, INSERM, F-75013 Paris, France.
authors.forename: Alexandre
authors.identifier: 0000-0001-6499-4540
authors.initials: A
authors.lastname: Borrel
authors.forename: Leo
authors.initials: L
authors.lastname: Ghemtio
authors.affiliation: Laboratoire Molécules Thérapeutiques in silico (MTi), UMRS-973, Université Paris Diderot , Sorbonne Paris Cité, INSERM, F-75013 Paris, France.
authors.forename: Leslie
authors.initials: L
authors.lastname: Regad
authors.forename: Gustav
authors.initials: G
authors.lastname: Boije Af Gennäs
authors.affiliation: Laboratoire Molécules Thérapeutiques in silico (MTi), UMRS-973, Université Paris Diderot , Sorbonne Paris Cité, INSERM, F-75013 Paris, France.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Camproux
authors.forename: Jari
authors.identifier: 0000-0003-0370-7653
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.forename: Henri
authors.initials: H
authors.lastname: Xhaard
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D030562:Databases, Protein; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D008024:Ligands; D010710:Phosphates