title: Human structural proteome-wide characterization of Cyclosporine A targets.
abstract: BACKGROUND
  Off-target interactions of a popular immunosuppressant Cyclosporine A (CSA) with several proteins besides its molecular target, cyclophilin A, are implicated in the activation of signaling pathways that lead to numerous side effects of this drug.
  
  
  RESULTS
  Using structural human proteome and a novel algorithm for inverse ligand binding prediction, ILbind, we determined a comprehensive set of 100+ putative partners of CSA. We empirically show that predictive quality of ILbind is better compared with other available predictors for this compound. We linked the putative target proteins, which include many new partners of CSA, with cellular functions, canonical pathways and toxicities that are typical for patients who take this drug. We used complementary approaches (molecular docking, molecular dynamics, surface plasmon resonance binding analysis and enzymatic assays) to validate and characterize three novel CSA targets: calpain 2, caspase 3 and p38 MAP kinase 14. The three targets are involved in the apoptotic pathways, are interconnected and are implicated in nephrotoxicity.
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Jody
authors.initials: J
authors.lastname: Groenendyk
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Khaled
authors.initials: K
authors.lastname: Barakat
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Marcin J
authors.initials: MJ
authors.lastname: Mizianty
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Jishou
authors.initials: J
authors.lastname: Ruan
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Marek
authors.initials: M
authors.lastname: Michalak
authors.affiliation: School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, PR China, Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada and State Key Laboratory for Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kurgan
mesh_terms: D000465:Algorithms; D002154:Calpain / Q000737:chemistry / Q000378:metabolism; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D020543:Proteome / Q000737:chemistry; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
chemical_list: D007166:Immunosuppressive Agents; D020543:Proteome; D016572:Cyclosporine; D048308:Mitogen-Activated Protein Kinase 14; D002154:Calpain; D053148:Caspase 3