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Distinct Conformations of Mirabegron Determined by MicroED
Jieye Lin1, Johan Unge1, Tamir Gonen1,2,3
1Department of Biological Chemistry, University of California, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 17, 2023
Summary
Mirabegron, a medication for overactive bladder, reveals its 3D structure and two distinct forms using MicroED. The drug undergoes significant conformational changes when binding to its receptor.
Area of Science:
- Pharmacology
- Structural Biology
- Crystallography
Background:
- Mirabegron (Myrbetriq) is a widely prescribed medication for overactive bladder syndrome.
- The three-dimensional (3D) structure and conformational behavior of Mirabegron upon receptor binding were previously unknown.
Purpose of the Study:
- To elucidate the 3D structure of Mirabegron.
- To investigate the conformational states of Mirabegron.
- To understand Mirabegron's conformational changes upon binding to the beta 3 adrenergic receptor (β3AR).
Main Methods:
- Microcrystal electron diffraction (MicroED) was employed to determine the structure of Mirabegron.
- Analysis of hydrogen bonding and crystal packing.
- Comparison of Mirabegron's structure alone and bound to β3AR.
Main Results:
- Mirabegron was found to adopt two distinct conformational states (conformers).
- Hydrophilic groups are embedded in the crystal lattice, leading to a hydrophobic surface and low water solubility.
- Conformers 1 and 2 exhibit trans- and cis- forms, respectively, and Mirabegron undergoes major conformational changes to bind the β3AR.
Conclusions:
- MicroED is effective for determining unknown and polymorphic structures of active pharmaceutical ingredients (APIs) from powders.
- The study reveals the structural basis for Mirabegron's properties and its interaction with the β3AR.
- Understanding these structural details can inform future drug design and development.
Keywords:
active pharmaceutical ingredientconformercrystallographymicrocrystal electron diffraction (microed)mirabegronMore Related Videos
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