Abstract
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 language | English |
|---|---|
| Journal | Journal of Chemical Information and Modeling |
| Volume | 57 |
| Issue number | 7 |
| Pages (from-to) | 1703-1714 |
| Number of pages | 12 |
| ISSN | 1549-9596 |
| DOIs | |
| Publication status | Published - 24 Jul 2017 |
Keywords
- Antifibrinolytic Agents
- Drug Discovery
- Fibrinolysin
- Isoxazoles
- Molecular Docking Simulation
- Piperidines
- Protein Domains
- Quantitative Structure-Activity Relationship
- Thermodynamics
- Journal Article