Center for Drug Design, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA.
Curr Top Med Chem. 2013;13(11):1257-72. doi: 10.2174/15680266113139990032.
Understanding the molecular basis of drug action has been an important objective for pharmaceutical scientists. With the increasing speed of computers and the implementation of quantum chemistry methodologies, pharmacodynamic and pharmacokinetic problems have become more computationally tractable. Historically the former has been the focus of drug design, but within the last two decades efforts to understand the latter have increased. It takes about fifteen years and over $1 billion dollars for a drug to go from laboratory hit, through lead optimization, to final approval by the U.S. Food and Drug Administration. While the costs have increased substantially, the overall clinical success rate for a compound to emerge from clinical trials is approximately 10%. Most of the attrition rate can be traced to ADMET (absorption, distribution, metabolism, excretion, and toxicity) problems, which is a powerful impetus to study these issues at an earlier stage in drug discovery. Quantum mechanics offers pharmaceutical scientists the opportunity to investigate pharmacokinetic problems at the molecular level prior to laboratory preparation and testing. This review will provide a perspective on the use of quantum mechanics or a combination of quantum mechanics coupled with other classical methods in the pharmacokinetic phase of drug discovery. A brief overview of the essential features of theory will be discussed, and a few carefully selected examples will be given to highlight the computational methods.
理解药物作用的分子基础一直是药物科学家的一个重要目标。随着计算机速度的不断提高和量子化学方法的实施，药效学和药代动力学问题变得更加易于计算。从历史上看，前者一直是药物设计的重点，但在过去二十年中，人们对后者的理解有所增加。一种药物从实验室发现到先导化合物优化，再到美国食品和药物管理局最终批准，大约需要 15 年和超过 10 亿美元的时间。尽管成本大幅增加，但化合物从临床试验中脱颖而出的总体临床成功率约为 10%。大部分损耗率可以追溯到 ADMET（吸收、分布、代谢、排泄和毒性）问题，这是在药物发现的早期阶段研究这些问题的强大动力。量子力学为药物科学家提供了在实验室准备和测试之前在分子水平上研究药代动力学问题的机会。本文将从药物发现的药代动力学阶段的角度，对量子力学或量子力学与其他经典方法相结合的应用进行综述。将讨论理论的基本特征的简要概述，并给出几个经过精心挑选的例子来突出计算方法。
