Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
The structure of hERG, an ion channel to which drugs should not bind, has been analysed by Roderick MacKInnon using cryo-electron microscopy. The hERG example suggests that structural information can contribute to toxicity avoidance. However, the resolution of all these hERG structures published to date is 3.8 Å, which is insufficient for structure-based calculations aimed at avoiding toxicity. The instrumental resolution of electron microscopes is as high as better than 1 Å, and the resolution for observing biological samples is limited by radiation damage but not by instrumental resolution. Since radiation damage to biological samples is significantly reduced by lowering the specimen temperature, cryo-electron microscopy is essential for SGDD: Structure-Guided Drug Development. Cryo-electron microscopy also allows high-resolution images to be taken of target molecules by embedding them in a thin layer of ice. For high-resolution data collections, 8th generation cryo-electron microscope was developed.
We are analysing drug target molecules including membrane proteins by single particle analysis utilising cryo-electron microscopy, and also challenging drug development based on SGDD. I believe SGDD may effectively help to avoid toxicity. Although there are still few examples of a drug rescuing strategy, where compounds that could not be developed into drugs due to toxicity or other reasons are rescued from the shelves of pharmaceutical companies, I would like to present an example of the rapid development of a potent infectious disease drug candidate based on SGDD.
