TY - JOUR
T1 - Discovery and Evaluation of Anti-Fibrinolytic Plasmin Inhibitors Derived from 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL)
AU - Schmidt, Thomas C.
AU - Eriksson, Per-Olof
AU - Gustafsson, David
AU - Cosgrove, David
AU - Frølund, Bente
AU - Boström, Jonas
PY - 2017/7/24
Y1 - 2017/7/24
N2 - 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).
AB - 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).
KW - Antifibrinolytic Agents
KW - Drug Discovery
KW - Fibrinolysin
KW - Isoxazoles
KW - Molecular Docking Simulation
KW - Piperidines
KW - Protein Domains
KW - Quantitative Structure-Activity Relationship
KW - Thermodynamics
KW - Journal Article
U2 - 10.1021/acs.jcim.7b00255
DO - 10.1021/acs.jcim.7b00255
M3 - Journal article
C2 - 28653850
SN - 1549-9596
VL - 57
SP - 1703
EP - 1714
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 7
ER -