Absolute configuration determination of SMTP-7 via microcrystal electron diffraction (MicroED).

Area of Science:

• Crystallography
• Drug Discovery
• Structural Chemistry

Background:

• Absolute configuration determination is crucial for drug candidates.
• The drug candidate SMTP-7 possesses five chiral centers, making its configuration analysis complex.
• Limited sample availability poses a significant challenge for traditional methods.

Purpose of the Study:

• To determine the absolute configuration of the drug candidate SMTP-7.
• To demonstrate the efficacy of Microcrystal Electron Diffraction (MicroED) for complex molecules.
• To showcase advanced MicroED techniques for challenging crystallographic problems.

Main Methods:

• Microcrystal Electron Diffraction (MicroED) analysis was employed.
• Kinematical refinement with additional chiral information was utilized.
• Direct dynamical refinement approach was applied.

Main Results:

• The absolute configuration of SMTP-7 was successfully assigned.
• MicroED proved effective for analyzing quantity-limited and complex molecules.
• Both kinematical and dynamical refinement approaches yielded unambiguous results.

Conclusions:

• MicroED is a powerful tool for absolute configuration determination of complex drug candidates.
• Advanced MicroED techniques overcome limitations of sample quantity and crystallizability.
• This study validates MicroED's utility in drug discovery and structural elucidation.