Bioscience Method 2024, Vol.15, No.2, 50-57 http://bioscipublisher.com/index.php/bm 54 how these changes affect the virus's replication and release processes. These insights are crucial for the development and optimization of antiviral drugs. They not only provide a structural basis for drug design but also offer important evidence for assessing drug efficacy and predicting drug resistance. Protein Degradation Drug Mechanism Elucidation: Through cryo-electron microscopy, Valle (2018) meticulously observed how drugs interact with key complexes in the protein degradation pathway and how they regulate the activity of these complexes. These findings involve the interaction patterns between drugs and complexes, drug-induced conformational changes, and how these changes affect the rate and selectivity of protein degradation. These discoveries are vital for understanding the regulatory mechanisms of protein homeostasis and provide new directions for developing drugs targeted at specific diseases. For example, in neurodegenerative diseases, regulating protein degradation processes can help clear harmful protein aggregates; in cancer therapy, inhibiting the degradation of specific proteins can enhance the efficacy of anticancer drugs. 2.3 How cryo-EM provides insights into drug interactions with biomolecules Cryo-electron microscopy (Cryo-EM) offers a powerful tool for revealing detailed information about the interactions between drugs and biomolecules through its unique imaging capabilities. Its working principle is based on rapidly freezing the sample under near-physiological conditions, thereby preserving the natural state and activity of biomolecules. Subsequently, under an electron microscope, these frozen samples are penetrated by a high-energy electron beam, which interacts with the atoms in the sample to produce scattering and absorption effects. These effects are then captured by an electron detector and converted into visible images. These images not only possess extremely high resolution but also capture the static and dynamic details of interactions between biomolecules and drug molecules. Through in-depth analysis of these images, the binding sites of drug molecules on biomolecules can be precisely determined, providing insights into how drugs interact with specific amino acid residues on biomolecules. Cryo-EM can also reveal conformational changes in biomolecules after drug binding, which may involve protein folding, domain rearrangement, or adjustments in overall structure, further elucidating how drugs affect the function of biomolecules (Twarock et al., 2018). In addition to providing static structural information, Cryo-EM can also capture the dynamic processes of drug interactions with biomolecules. This includes how drug molecules gradually approach and ultimately bind to biomolecules, and how binding triggers a series of biological effects. This dynamic observation provides key clues for understanding the comprehensive mechanisms of drug action, helping to more fully comprehend how drugs function at the cellular level. 3 Impact of Cryo-Electron Microscopy on Drug Discovery and Design 3.1 Application of cryo-electron microscopy in drug screening and optimization Cryo-electron microscopy (cryo-EM) has broad applications in the drug screening and optimization process. During the drug screening phase, cryo-EM can provide high-resolution images of the interaction between candidate drugs and biological macromolecular targets. This helps researchers quickly identify potential drugs. By observing and comparing the binding modes and affinities of different drugs to the targets, it can be preliminarily determined which drugs are worth further in-depth study (Twarock and Stockley, 2019). In the drug optimization phase, cryo-EM can reveal detailed mechanisms of interaction between drugs and biomolecules. This includes how drugs affect the conformation, function, and signaling pathways of the targets. By studying these interaction details extensively, the structure of drugs can be optimized, their efficacy improved, and potential side effects reduced. The data provided by cryo-EM offers significant theoretical support and experimental evidence for drug improvements (Michael et al., 2021). Cryo-EM can also be used to evaluate drug resistance. The emergence of resistance is a common challenge in drug development. By using cryo-EM to observe the interactions between drugs and resistant mutants, a deeper understanding of resistance mechanisms can be gained. This knowledge allows for the design of new drug strategies to overcome resistance, providing new ideas and methods for drug development and clinical treatment.
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