Conformational study on telaprevir by HPLC-DAD-MS and theoretical calculation
Xiuying Sun1, Yuan Jiang1, Xiulian Ju2
1Department of Pharmacy, Tianjin Union Medical Center, Tianjin, People's Republic of China.
Biomedical Chromatography : BMC
|July 6, 2019
Summary
Telaprevir, an inhibitor of hepatitis C virus (HCV) protease, undergoes E-Z isomerization in solution. The minor Z-isomer exhibits greater binding affinity and inhibitory activity against HCV NS3-4A protease.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Structural Biology
Background:
- Telaprevir is a key peptidomimetic inhibitor targeting the hepatitis C virus (HCV) NS3-4A serine protease.
- It is clinically used in combination therapy for HCV infection.
Purpose of the Study:
- To investigate the E-Z isomerization of telaprevir in solution.
- To elucidate the structural and binding characteristics of telaprevir isomers with HCV NS3-4A protease.
Main Methods:
- Online High-Performance Liquid Chromatography-Diode Array Detector-Mass Spectrometry (HPLC-DAD-MS).
- Variable-temperature and variable-gradient experiments.
- Molecular mechanics calculations and molecular docking.
Main Results:
- The E-Z isomerization process of telaprevir in solution was successfully characterized.
- Molecular mechanics revealed distinct geometric information for the E and Z isomers.
- Molecular docking demonstrated differential binding affinities, with the Z-isomer showing higher affinity to HCV NS3-4A protease.
Conclusions:
- The Z-isomer of telaprevir, despite being the minor form in solution, is a more potent inhibitor of HCV NS3-4A protease.
- Understanding telaprevir isomerism provides crucial structural insights for drug design and understanding protease binding.
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