5 years ago

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

Discovery and Evaluation of Anti-Fibrinolytic Plasmin Inhibitors Derived from 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL)
Jonas Boström, Per-Olof Eriksson, Thomas C. Schmidt, Bente Frølund, David Cosgrove, David Gustafsson
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 (R2 = 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 (R2 = 0.6).

Publisher URL: http://dx.doi.org/10.1021/acs.jcim.7b00255

DOI: 10.1021/acs.jcim.7b00255

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