Success in Developing a New Evaluation Method for Compounds that Affect Polymerizing Proteins —Possible Method for Discovering New Treatment Drugs for Neurodegenerative Diseases—
Research Press Release | July 14, 2015
|Key Points||・ In order to develop new antibacterial drugs, our investigation was to discover compounds that inhibit the protein polymerization that is necessary for bacterial growth.
・ By using computer virtual screening and innovated spectroscopic methods, six compounds were found out from a library of about 210,000 library of compounds. Of these, one compound was actually verified to have antibacterial action.
・ This research is expected to provide a method for discovering new drugs for neurodegenerative diseases that are caused by protein polymerization within neurons.
It is necessary for the FtsZ 1 protein to polymerize for bacterial cell division. Thus, chemical compounds that inhibit FtsZ protein polymerization are candidates for new antibacterial drugs 2. In order to find the compounds that inhibit polymerization of the FtsZ protein, we established a screening method that uses virtual screening by computer simulation as well as fluorescence cross-correlation spectroscopy (FCCS) 3. By using this screening method, 71 candidates for compounds that inhibit the polymerization of the FtsZ protein were found from a library of about 210,000 compounds. Among these, further investigation of six compounds that particularly showed the ability to inhibit polymerization of FtsZ protein, one compound actually showed antibacterial activity against Staphylococcus aureus.
1) FtsZ (filamenting temperature-sensitive mutant Z): A protein that is homologous to the tubulin of animal cells. This is the first cytoskeleton protein discovered in prokaryotic cells. It exhibits GTP-dependent polymerization and cooperates with other proteins to form a contractile ring structure during cell division.
2) Antibacterial drug: General name for a drug that acts to inhibit bacterial growth and a germicide. Originally, this was synonymous with an antibiotic (antibiotic = antibacterial drug). However, more recently, “antibiotic” has come to include, not just compounds that have antibacterial action, but also compounds that have antifungal, antiparasitic, antiviral, or anticancer action. Antibacterial drugs have become a subset of antibiotics.
3) Fluorescence cross-correlation spectroscopy (FCCS): FCCS is based on fluorescence correlation spectroscopy (FCS). FCS is a method for studying fluorescent-labeled biological molecules by analysis of fluorescent fluctuations that occur when fluorescent molecules enter and leave a tiny focal region formed by a confocal optical system. FCS can quantify “motion” and “number” at the single molecules level, as well as dynamic “molecular interactions”. FCCS is expanded from FCS by using two colors of fluorescent. Thus, FCCS can directly quantify molecular interactions by analyzing the coincident of florescence intensities, but also “motion” and “number” information for each of the fluorescent-labeled biological molecules.
4) Hokkaido University Academic Cloud: An aggregate of virtual machines mediated via the internet. This is one of the largest academic cloud systems in Japan, having a total computing capability of 43 TFLOPs and the ability to form more than 2,000 virtual machines. The present research performed virtual screening by using part of this cloud (120 cores).
5) University of Tokyo Drug Discovery Initiative Compound Library: A large-scale library containing more than 200,000 compounds, constructed as a project of the Platform for Drug Discovery, Informatics, and Structural Life Science of the Ministry of Education, Culture, Sports, Science, and Technology. It also provides a compound database, and present research is able to perform virtual as well as actual screening by using this database.
Coordinating Office, Future Drug Discovery and Medical Care Innovation Project, Hokkaido University
Publicity liaison: Ms. Wada
|Publications||Screening for FtsZ Dimerization Inhibitors Using Fluorescence Cross-Correlation Spectroscopy and Surface Resonance Plasmon Analysis, PLOS ONE (2015.7.9)|