Structural Analysis Using Cryo-electron Microscopy for Protein-based Drug Design

Structure-based drug design (SBDD) plays a crucial role in modern drug discovery. SBDD is a methodology that utilizes the three-dimensional (3D) structural information of a target protein to computationally search for compounds that bind to it and/or to optimize the binding of known compounds. This article provides an overview of recent advances in SBDD. Furthermore, we introduce 2 case studies conducted by the authors using single-particle analysis via Cryo-electron microscopy (Cryo-EM), a powerful technique for obtaining protein structures. The first example is the sodium ion (Na+)-translocating NADH-quinone oxidoreductase derived from Vibrio cholerae. This enzyme is suggested to undergo large conformational changes during the reaction cycle. By performing classification in single-particle analysis, we successfully captured a partial view of these conformational dynamics. The second example involves the angiotensin-converting enzyme 2 (ACE2) decoy, which binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and inhibits infection. Focusing on ACE2, which is critical for SARS-CoV-2 infection, an ACE2 decoy was developed to achieve higher binding affinity than the wild-type ACE2. We successfully elucidated how this ACE2 decoy binds to the spike protein.