Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor

Xiaozhen Wang; Yuji Wang; Jianhui Wu; Lin Gui; Xiaoyi Zhang; Meiqing Zheng; Yaonan Wang; Shurui Zhao; Ze Li; Ming Zhao; Shiqi Peng

doi:10.1016/j.bmcl.2017.10.068

Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5114-5118. doi: 10.1016/j.bmcl.2017.10.068. Epub 2017 Oct 28.

Authors

Xiaozhen Wang¹, Yuji Wang¹, Jianhui Wu¹, Lin Gui¹, Xiaoyi Zhang¹, Meiqing Zheng¹, Yaonan Wang¹, Shurui Zhao¹, Ze Li¹, Ming Zhao², Shiqi Peng³

Affiliations

¹ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
² Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: mingzhao@bjmu.edu.cn.
³ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China. Electronic address: sqpeng@bjmu.edu.cn.

PMID: 29108753
DOI: 10.1016/j.bmcl.2017.10.068

Abstract

In GPIIb/IIIa mediated arterial thrombosis platelet activation plays a central role. To discover platelet activation inhibitor the pharmacophores of GPIIb/IIIa receptor inhibitors and anti-thrombotic agents were analyzed. This led to the design of (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids as GPIIb/IIIa inhibitors. Comparing to (1S,3S)-isomer (1R,3S)-isomer had lower cdocker interaction energy. AFM image showed that the minimal effective concentration of (1S,3S)-isomer and (1R,3S)-isomer inhibiting platelet activation were 10^-5 M and 10^-6 M, respectively. In vivo 1 μmol/kg of oral (1S,3S)-isomer effectively inhibited the rats to form arterial thrombus and down regulated GPIIb/IIIa expression, but the activities were significantly lower than those of 1 μmol/kg of oral (1R,3S)-isomer. Both (1S,3S)-isomer and (1R,3S)-isomer can be safely used for structural modifications, but (1R,3S)-isomer should be superior to (1S,3S)-isomer.

Keywords: Docking; GPIIb/IIIa; Inhibitor; Platelet activation; Thrombosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Binding Sites
Blood Platelets / drug effects
Blood Platelets / metabolism
Drug Design*
Microscopy, Atomic Force
Molecular Docking Simulation
Platelet Aggregation Inhibitors / chemistry*
Platelet Aggregation Inhibitors / pharmacology
Platelet Aggregation Inhibitors / therapeutic use
Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
Protein Structure, Tertiary
Rats
Stereoisomerism
Thermodynamics
Thiazoles / chemistry*
Thiazoles / pharmacology
Thiazoles / therapeutic use
Thrombosis / drug therapy

Substances

Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Thiazoles
2-methylthiazolidine-4-carboxylic acid