title: Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic acid.
abstract: Protein-protein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles. One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhibits binding of plasminogen to fibrin. However, the daily dose of TXA is high due to its modest potency and pharmacokinetic properties. In this study, we report a computational approach, where the focus was on finding electrostatic potential similarities to TXA. Coupling this computational technique with a high-quality low-throughput screen identified 5-(4-piperidyl)-3-isoxazolol (4-PIOL) as a potent plasminogen binding inhibitor with the potential for the treatment of various bleeding disorders. Remarkably, 4-PIOL was found to be more than four times as potent as the drug TXA.
authors.affiliation: AstraZeneca Mölndal, CVGI iMed, Mölndal, Sweden. jonas.bostrom@astrazeneca
authors.forename: Jonas
authors.initials: J
authors.lastname: Boström
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Grant
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
authors.forename: Anders
authors.initials: A
authors.lastname: Thelin
authors.forename: David
authors.initials: D
authors.lastname: Gustafsson
mesh_terms: D000933:Antifibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D055672:Static Electricity; D014148:Tranexamic Acid / Q000494:pharmacology
chemical_list: D000933:Antifibrinolytic Agents; D007555:Isoxazoles; D010880:Piperidines; C073009:5-(4-piperidyl)isoxazol-3-ol; D014148:Tranexamic Acid; D010958:Plasminogen