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Discovery and Evaluation of Anti-Fibrinolytic Plasmin Inhibitors Derived from 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL)

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Thomas C. Schmidt, Per-Olof Eriksson, David Gustafsson, David Cosgrove, Bente Frølund, Jonas Boström

Inhibition of plasmin has been found to effectively reduce fibrinolysis and to avoid hemorrhage. This can be achieved by addressing its kringle 1 domain with the known drug and lysine analogue tranexamic acid. Guided by shape similarities toward a previously discovered lead compound, 5-(4-piperidyl)isoxazol-3-ol, a set of 16 structurally similar compounds was assembled and investigated. Successfully, in vitro measurements revealed one compound, 5-(4-piperidyl)isothiazol-3-ol, superior in potency compared to the initial lead. Furthermore, a strikingly high correlation (R(2) = 0.93) between anti-fibrinolytic activity and kringle 1 binding affinity provided strong support for the hypothesized inhibition mechanism, as well as revealing opportunities to fine-tune biological effects through minor structural modifications. Several different ligand-based (Freeform, shape, and electrostatic-based similarities) and structure-based methods (e.g., Posit, MM/GBSA, FEP+) were used to retrospectively predict the binding affinities. A combined method, molecular alignment using Posit and scoring with Tcombo, lead to the highest coefficient of determination (R(2) = 0.6).

Original languageEnglish
JournalJournal of Chemical Information and Modeling
Issue number7
Pages (from-to)1703-1714
Number of pages12
Publication statusPublished - 24 Jul 2017

    Research areas

  • Antifibrinolytic Agents, Drug Discovery, Fibrinolysin, Isoxazoles, Molecular Docking Simulation, Piperidines, Protein Domains, Quantitative Structure-Activity Relationship, Thermodynamics, Journal Article

ID: 185654433