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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
PubMed
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.

Keywords:
HCV proteaseMicroEDmacrocyclesmolecular chameleonspolymorphism

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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.