Mechanism and inhibition kinetics of peptide P13 as thrombin inhibitor.

Fangyuan Chen, Guangrong Huang

International journal of biological macromolecules 2020 May 01

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Excessive coagulation can easily lead to arterial and venous thrombosis, which is the main reason for the evolution of myocardial infarction and cerebrovascular accidents. As a key coagulation factor for the coagulation pathway, thrombin has become a remarkable target for the control of thrombosis. The synthesized peptide P13 with amino acid sequence of N-RGDAGFAGDDAPR was expected to be an inhibitor with higher antithrombotic activity. The results showed that the IC50 (50% inhibition of thrombin activity) of the peptide P13 was determined by colorimetric method to be 115 µM. And enzyme kinetic experiments showed that P13 was a competitive inhibitor of thrombin with Ki = 106 µM. Fluorescence spectra and three-dimensional fluorescence showed that P13 could alter the secondary structure of thrombin and the microenvironment of certain chromogenic amino acids. P13 can spontaneously bind with thrombin exosite 1 in the form of 1:1 mainly through hydrogen bonding and van der Waals force. And the optimal docking mode of P13 and thrombin was revealed by molecular docking with "-CDOCKER_Energy" of 178.679 kcal mol-1. This study revealed P13 may become a potential anticoagulant drug widely used after further studies in preclinical and clinical trials. Copyright © 2019 Elsevier B.V. All rights reserved.

Citation

Fangyuan Chen, Guangrong Huang. Mechanism and inhibition kinetics of peptide P13 as thrombin inhibitor. International journal of biological macromolecules. 2020 May 01;150:1046-1052