Study Of The Catalytic Mechanism On P300and Anti-bacterium Small Molecule Design

Computer aided drug design (CADD) is a computer-based drug design method,which uses computer to simulate, calculate and predict the interactions between drugmolecules and biological macromolecules. Therefore, CADD provides much informationfor lead compounds optimization and design. Generally, CADD contains Structure-baseddrug design and Ligand-based drug design. In recent years, with enhancing of thecomputer calculating capability， molecular dynamics and quantum mechanics play moreand more important role t in CADD, for example, in the study of reaction mechanism,optimization of the molecular conformation, and the reaction route inferring. In this study,we used several of CADD methods and techniques to optimize the biologicalmacromolecules, predict the reaction mechanism and design small antibacterial drugmolecules. These studies were divided into two parts.In the first part, we use the molecular dynamics, quantum mechanics/molecularmechanics to investigate the acetylation reaction mechanism and the transfer route of p300histone. We constructed three p300models(no substrate, containing all substrates and part of the region missing substrates), then100ns MD simulation was used for every model toresearch the stability of p300key region and the interaction with surroundings;mechanism of missing part of the region leading to enzyme inactivation; mechanism of thesubstrate binding as well. At last, we revealed the several important steps of p300acetylation reaction and proposed a reasonable proton transfer mechanism.In the second part, according to the theory of ligand-based drug design QSAR andsimilar property principle, making use of methods such as scaffold hopping, combiningwith chemical informatics and systems biology information and technology, wediscovered new chemistry entity compounds by transforming molecular structure ofclinical drug which was used to treat bacteria infection sparked by Candida albicans andStaphylococcus aureus Gram-positive bacteria. Some of the compounds were verifiedowing good biological activity after a series of testing.