Molecular Modeling in Drug Design for the Development of Organophosphorus Antidotes/Prophylactics

摘要

This contract is aimed at solving the 3-dimensional structure of acetylcholinesterase. The structural data will facilitate the drug design against the acetylcholinesterase inhibitors by molecular modeling and theoretical prediction in the action of drugs. In the first year, we implemented the biochemical procedures for purifying acetylcholinesterase from electric eel. We had preliminary success in making small crystals from the purified proteins. Computer programs for reconstructing three-dimensional structure from electron images were developed. In the second year, we focused our effort on recording electron images of the isolated acetylcholinesterase molecules and of the thin crystals of acetylcholinesterase. Electron images of these specimens at various angles of tilt have been recorded for use in reconstructing the enzyme's 3-dimensional structure. In the third year, we succeeded in crystallizing the acetylcholinesterase suitable for X-ray diffraction analysis to 4A resolution. (aw)