Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED

Area of Science:

• Structural biology
• Drug discovery
• Crystallography

Background:

• Paritaprevir is a macrocyclic drug for Hepatitis C virus (HCV) infection.
• Its detailed structure was previously unknown, hindering drug optimization.
• Polymorphism can affect drug bioavailability and efficacy.

Approach:

• Microcrystal Electron Diffraction (MicroED) was used to determine the structures of two paritaprevir polymorphs.
• Molecular docking was performed to assess binding interactions with the NS3/4A serine protease.
• Conformational differences in the macrocyclic core and substituents were analyzed.

Key Points:

• Two distinct polymorphic crystal forms of paritaprevir were solved from a single experiment using MicroED.
• Observed conformational variations in the macrocyclic core and substituents.
• One paritaprevir conformation showed favorable binding to the NS3/4A serine protease active site.

Conclusions:

• The study demonstrates MicroED's capability to resolve multiple polymorphs and conformations simultaneously.
• Structural insights aid in optimizing acylsulfonamide inhibitors for HCV NS3/4A serine protease.
• Findings contribute to a deeper understanding of paritaprevir's structure-activity relationship.