Bioscience Method 2024, Vol.15, No.2, 50-57 http://bioscipublisher.com/index.php/bm 52 For example, in the study of drug action mechanisms, cryo-electron microscopy can reveal the binding patterns of drug molecules to biological macromolecular targets and the conformational changes in biological macromolecules caused by drugs. This information is crucial for understanding the mechanisms of drug action, optimizing drug design, and discovering new drugs. The application of cryo-electron microscopy in the structural analysis of biological macromolecules not only broadens our understanding of the structure and function of biological macromolecules but also provides significant support for the development of the pharmaceutical research field. 1.3 Applicability of cryo-EM technology in elucidating mechanisms of drug action Cryo-electron microscopy (Cryo-EM) technology has broad applicability in elucidating the mechanisms of drug action. Whether dealing with small molecule drugs or biological macromolecules, this technology can provide key structural and dynamic information, helping to deeply understand the mechanisms of drug action. It allows for imaging of biological macromolecules under near-physiological conditions, meaning it can observe the interactions between drugs and biological macromolecules in a state close to their natural state. The structures of biological macromolecules under these conditions are usually more authentic, hence making the drug mechanism information obtained more reliable (Nannenga and Gonen, 2018). The high-resolution images provided by Cryo-EM technology enable the capture of fine details of the interactions between drugs and biological macromolecules. These details may involve the precise binding sites of the drug molecules, modes of binding, and the consequent conformational changes in the biological macromolecules. This information is crucial for understanding the mechanisms of drug action as they reveal how drugs interact with biological macromolecules to produce therapeutic effects or side effects (Hutchings et al., 2018). Cryo-EM technology also captures the dynamic changes of biological macromolecules under the influence of drugs. This dynamic observation provides important information about how drugs affect the functions of biological macromolecules, including drug-induced signaling pathways and conformational transitions of the macromolecules. This information is essential for understanding the comprehensive mechanisms of drug action as they reveal the complex processes of drug actions within biological systems. 2 Practical Applications of Cryo-EM in the Analysis of Drug Mechanisms of Action 2.1 Cases of successful resolution of drug mechanisms using cryo-EM 2.1.1 Analysis of the drug mechanism of G protein-coupled receptors (GPCRs) GPCRs are a significant class of drug targets involved in various physiological and pathological processes. Using cryo-electron microscopy, Daniel and José (2020) successfully resolved the three-dimensional structures of multiple GPCRs bound with drugs, revealing how drugs bind to and either activate or inhibit their activity. These studies not only help understand the drug mechanisms of GPCRs but also provide essential guidance for the design and optimization of drugs targeting these receptors. 2.1.2 Analysis of antiviral drug mechanisms Cryo-EM has also been widely used in the study of antiviral drug mechanisms. For example, Zhu et al. (2021) utilized this technique to analyze the binding mechanism of the influenza virus neuraminidase with the antiviral drug oseltamivir and the structure of the N501Y spike protein of the novel coronavirus complexed with ACE2 and two effective neutralizing antibodies. This analysis provided a detailed glimpse into the cryo-EM structure of the complex formed between the extracellular domain of the N501Y spike protein and the extracellular domain of the ACE2 receptor, revealing how the drug inhibits the viral replication process (Figure 2). This offers new insights and approaches for the design and development of antiviral drugs. 2.1.3 Analysis of protein degradation drug mechanisms Protein degradation plays a crucial role within the cell, and drug development targeting protein degradation processes has always been a hot area. Cryo-EM has successfully resolved the binding patterns of various protein degradation-related complexes with drugs, such as the interactions between key proteins in the ubiquitin-proteasome system and the autophagy pathway with drugs. These studies not only aid in understanding
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