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Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED
Guanhong Bu1, Emma Danelius1,2, Lianne H E Wieske3
1Department of Biological Chemistry, University of California Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
Advanced Biology
|February 21, 2024
Summary
Microcrystal electron diffraction revealed two crystal forms of the Hepatitis C virus drug paritaprevir. These distinct structures show conformational changes, aiding in optimizing drug binding to the HCV protease target.
Area of Science:
- Structural biology
- Drug discovery
- Crystallography
Background:
- Paritaprevir is an orally bioavailable macrocyclic drug for chronic Hepatitis C virus (HCV) infection.
- The precise structures of paritaprevir have been challenging to determine until recent advancements.
Purpose of the Study:
- To elucidate the distinct polymorphic crystal structures of paritaprevir using MicroED.
- To investigate conformational variations within these polymorphs and their implications for drug-target interactions.
Main Methods:
- Microcrystal electron diffraction (MicroED) was employed to solve the structures of two distinct paritaprevir polymorphs.
- Molecular docking simulations were performed to assess the binding of paritaprevir conformations to the HCV NS3/4A serine protease.
Main Results:
- Two distinct polymorphic crystal forms of paritaprevir were successfully resolved from a single experiment.
- Conformational changes were observed in the macrocyclic core and substituents across the different polymorphs.
- Molecular docking indicated favorable binding of one paritaprevir conformation within the active site of the HCV NS3/4A serine protease, involving hydrophobic and hydrogen bond interactions.
Conclusions:
- The study demonstrates the utility of MicroED in deriving multiple polymorphs and macrocycle conformations from the same experimental setup.
- The structural insights gained can inform the optimization of acyl sulfonamide inhibitors targeting the HCV NS3/4A serine protease.
- Understanding these structural variations is crucial for the development of more effective Hepatitis C treatments.
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