Zheng Fang, Zhan Chang-Guo
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA.
Org Biomol Chem. 2008 Mar 7;6(5):836-43. doi: 10.1039/b716268e. Epub 2007 Dec 5.
(-)-Cocaine is a widely abused drug and there is currently no available anti-cocaine therapeutic. Promising agents, such as anti-cocaine catalytic antibodies and high-activity mutants of human butyrylcholinesterase (BChE), for therapeutic treatment of cocaine overdose have been developed through structure-and-mechanism-based design and discovery. In particular, a unique computational design strategy based on the modeling and simulation of the rate-determining transition state has been developed and used to design and discover desirable high-activity mutants of BChE. One of the discovered high-activity mutants of BChE has a approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the structure-and-mechanism-based design and discovery effort demonstrates that the unique computational design approach based on transition state modeling and simulation is promising for rational enzyme redesign and drug discovery. The general approach of the structure-and-mechanism-based design and discovery may be used to design high-activity mutants of any enzyme or catalytic antibody.
（-）-可卡因是一种被广泛滥用的药物，目前尚无可用的抗可卡因治疗方法。通过基于结构和机制的设计与发现，已经开发出了有前景的药物，如抗可卡因催化抗体和人丁酰胆碱酯酶（BChE）的高活性突变体，用于治疗可卡因过量。特别是，已经开发出一种基于限速过渡态建模和模拟的独特计算设计策略，并用于设计和发现理想的BChE高活性突变体。所发现的BChE高活性突变体之一对（-）-可卡因的催化效率提高了约456倍。基于结构和机制的设计与发现工作取得的令人鼓舞的成果表明，基于过渡态建模和模拟的独特计算设计方法在合理的酶重新设计和药物发现方面具有前景。基于结构和机制的设计与发现的一般方法可用于设计任何酶或催化抗体的高活性突变体。
