4/16/2024 0 Comments Discovery life go com activate![]() Cryo-EM is mainly used to analyze the structures of macromolecules larger than approximately 100 kD, and most cryo-EM structures with higher resolution than 3 Å are characterized as larger than 135 kD. However, it requires the labelling of protein backbone and/or amino acid residues with NMR-sensitive isotopes and is limited to small proteins below 50 kD. On the other hand, without crystallization, NMR can directly analyze the structure of proteins in solution and provide valuable information about internal protein dynamics. In addition, for membrane proteins, obtaining high-quality crystal structures is still full of uncertainties. As the yield of proper crystals becomes increasingly difficult with increasing molecular size, there are only a few crystal structures of target proteins beyond 150 kD and super-large protein complexes. However, X-ray crystallography mostly covers protein molecules and molecular complexes with a size of approximately 10–150 kD. X-ray crystallography usually provides structural information at the atomic level, which has obvious advantages for crystallizable macromolecules. Presently, there are three predominant techniques for the study of structural biology, namely, X-ray crystallography, nuclear magnetic resonance (NMR), and cryogenic electron microscopy (cryo-EM). Based on atomic resolution information about the active or regulatory sites of target proteins, the structural design of drugs becomes practical. Structural biology has always played an important role in drug discovery since it provides the most direct and visible atomic-level information on drug targets, and it can be applied to every step of preclinical drug development, including the identification and design of drug targets and the optimization of lead compounds. Presently, several of the most prevalent drug screening methods include the high-throughput screening of compound libraries and technologies such as structure-based drug design (SBDD), fragment-based drug discovery (FBDD), DNA-encoded chemical library, proteolysis targeting chimera (PROTAC) and drug repurposing, which account for an increasing proportion of contemporary drug development. With further improvements in drug development strategies, new drug screening platforms have emerged based on traditional technologies. The current drug design and discovery process is more directional and visible and requires a high degree of joint effort across multiple disciplines. Since the late twentieth century, breakthroughs in molecular biology, synthetic chemistry, structural biology, and computational techniques have brought great changes to the field of novel drug research and development. There are many interesting examples, including the discovery of the antibacterial activity of penicillin and sulfonamides, and the large-scale screening of natural products to identify the antitumor drug paclitaxel and the antimalarial drug artemisinin. Early drug discovery and development mainly stemmed from accidental discovery and natural product screening. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.ĭrug discovery is closely related to human health. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Structural biology has been demonstrated as a powerful tool to accelerate drug development. ![]() Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. ![]()
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