Rational Design of Inhibitors of Yersinia pestis EF-Tu

描述（由研究者提供）：缺乏可靠的广谱抗生素和危险病原体中迅速出现的抗生素耐药性对人类健康构成直接威胁，并引起重大生物防御问题。迫切需要不受耐药性影响并靶向细菌中高度保守的功能关键分子位点的新型抗微生物化合物。延伸因子Tu（EF-Tu）是广泛反应性抗菌剂的最佳靶标：EF-Tu具有至少三个功能相关的结合口袋，这些结合口袋在许多细菌物种中基本上相同，包括大肠杆菌。coli、S.鼠伤寒沙门氏菌（S.福氏杆菌、霍乱弧菌和鼠疫菌。最近由加州大学欧文分校的Frances Jurnak博士解决，EF-Tu蛋白与天然抗生素共结晶的3D结构解释了这些分子抑制剂活性的原子细节，并为合理设计新的，安全有效的抗菌剂提供了坚实的基础。我们的应用程序结合了Jurnak博士的结构研究与Molsoft最先进的灵活对接和虚拟配体筛选能力，以及化学多样性实验室在平行合成，生化和生物测定方面的专业知识，以快速，结构为重点的方式发现新的抗生素。

DESCRIPTION (provided by investigator): The lack of reliable wide-spectrum antibiotics and rapid emergence of antibiotic resistance in dangerous pathogens poses immediate threats for human health generally and major biodefense concerns. Novel classes of antimicrobial compounds uncompromised by resistance and targeting highly conserved, functionally critical molecular sites in bacteria are urgently needed. Elongation Factor Tu (EF-Tu) is an optimal target for broadly reactive antimicrobials: EF-Tu has at least three functionally relevant binding pockets essentially identical among many bacterial species, including E. coli, S. typhimurium and S. flexneri, V. cholerae, and plague agent Yersinia Pestis. Recently solved by Dr. Frances Jurnak, UC-Irvine, the 3D structures of EF-Tu protein co-crystallized with natural antibiotics explain the atomic details of inhibitor activity of these molecules and provide a solid basis for rational design of new, safe and effective antimicrobials. Our application combines Dr. Jurnak's structural studies with Molsoft's state of the art flexible docking and virtual ligand screening capabilities, and Chemical Diversity Laboratories' expertise in parallel synthesis, biochemical and biological assays to discover new antibiotics in a rapid, structure-focused manner.