title: Discovering novel chemical inhibitors of human cyclophilin A: virtual screening, synthesis, and bioassay.
abstract: Cyclophilin A (CypA) is a member of cyclophilins, a family of the highly homologous peptidyl prolyl cis-trans isomerases (PPIases), which can bind to cyclosporin A (CsA). CypA plays critical roles in various biological processes, including protein folding, assembly, transportation, regulation of neuron growth, and HIV replication. The discovery of CypA inhibitor is now of a great special interest in the treatment of immunological disorders. In this study, a series of novel small molecular CypA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. The SPECS_1 database containing 85,000 small molecular compounds was searched by virtual screening against the crystal structure of human CypA. After SPR-based binding affinity assay, 15 compounds were found to show binding affinities to CypA at submicro-molar or micro-molar level (compounds 1-15). Seven compounds were selected as the starting point for the further structure modification in considering binding activity, synthesis difficulty, and structure similarity. We thus synthesized 40 new small molecular compounds (1-6, 15, 16a-q, 17a-d, and 18a-l), and four of which (compounds 16b, 16h, 16k, and 18g) showed high CypA PPIase inhibition activities with IC50s of 2.5-6.2 microM. Pharmacological assay indicated that these four compounds demonstrated somewhat inhibition activities against the proliferation of spleen cells.
authors.affiliation: Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019992:Databases as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D011237:Predictive Value of Tests; D011487:Protein Conformation; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D021984:Cyclophilin A