COMPUTATIONAL DESIGN OF HAPTENS TO DESTROY COCAINE

这项研究的最终目标是利用理论和实验之间的协同作用来设计一种分子，该分子将成功诱导催化抗体，其对可卡因的水解速率提高超过100，000倍。量子力学计算的结果将用于改进分子的设计，称为诱导抗体的半抗原。我的合作者，哥伦比亚大学内科和外科医生学院的唐纳德·兰德里博士，将合成设计好的半抗原，并测试它们产生催化抗体的能力。我们将开始通过确定所需的理论，以准确地模拟现有的结构和动力学数据的适当水平。然后，我们将使用确定的方法来模拟可卡因的分子内水解。通过比较过渡态的分子静电势（MEP）与不同半抗原的MEP，我们将能够识别最接近实际过渡态的半抗原。与过渡态结构最相似的半抗原将用于产生催化抗体。将抗体催化效率与量子力学预测相关联将确定从量子化学中获得的关键见解，并增强我们对如何产生最有效的催化抗体的理解。了解如何引出最有效的催化抗体将对科学界产生广泛的影响。该项目将增加我们对催化抗体用于治疗药物添加的潜力的理解。

The ultimate goal of this research is to use the synergy between theory and experiment to design a molecule that will successfully induce catalytic antibodies having greater than 100,000-fold rate enhancement for the hydrolysis of cocaine. The results of quantum mechanical calculations will be used to refine the design of molecules, known as haptens that induce antibodies. My collaborator, Dr. Donald Landry, at the Columbia University College of Physicians and Surgeons, will synthesize the designed haptens and test their ability to generate catalytic antibodies. We will begin by identifying the appropriate level of theory needed to accurately model the available structural and kinetic data. We will then use the identified approach to model the intramolecular hydrolysis of cocaine. By comparing the molecular electrostatic potential (MEP) of the transition state with MEPs for different haptens, we will be able to identify the haptens that are closest to the actual transition state. The haptens most closely resembling the transition state structure will be used to generate catalytic antibodies. Correlating antibody catalytic efficiency with quantum mechanical predictions will identify the key insights obtainable from quantum chemistry, and enhance our understanding of how to generate the most efficient catalytic antibodies. Understanding how to elicit the most efficient catalytic antibodies would have wide- ranging implications for the scientific community. This project will increase our understanding of the potential for catalytic antibodies to be used for the treatment of drug addition.