Cryo-EM: The Resolution Revolution and Drug Discovery

Area of Science:

• Structural biology
• Biophysics
• Drug discovery

Background:

• Cryo-electron microscopy (cryo-EM) has advanced significantly due to technological innovations.
• The drug discovery field initially viewed cryo-EM with skepticism but now recognizes its transformative potential.
• Understanding complex molecular targets is crucial for developing novel therapeutics.

Purpose of the Study:

• To critically assess the impact of cryo-EM on drug discovery across various therapeutic areas.
• To review specific examples of previously intractable targets now amenable to structure-based drug design.
• To highlight the achievements, challenges, and limitations of cryo-EM in drug discovery.

Main Methods:

• Review of scientific literature focusing on cryo-EM applications in drug discovery.
• Analysis of case studies involving membrane proteins and multiprotein complexes.
• Discussion of technological advancements driving cryo-EM's utility.

Main Results:

• Cryo-EM has enabled structure determination for challenging targets like GABA_A receptors, TRP channels, and G protein-coupled receptors.
• The technique has provided molecular insights into large complexes such as ribosomes, the proteasome, and eIF2B.
• Structure-based drug design has been significantly advanced for these previously intractable targets.

Conclusions:

• Cryo-EM has become a mainstream technique in structural biology, profoundly impacting drug discovery.
• The application of cryo-EM has expanded the scope of structure-based drug design to a wider range of critical biological targets.
• Continued advancements in cryo-EM promise further breakthroughs in therapeutic development.