量子化学在制药工艺开发中的应用：现状与机遇,Organic Process Research & Development

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量子化学在制药工艺开发中的应用：现状与机遇
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-07-23 , DOI: 10.1021/acs.oprd.0c00222
Yu-hong Lam ₁ , Yuriy Abramov ₂ , Ravi S. Ananthula ₃ , Jennifer M. Elward ₄ , Lori R. Hilden ₅ , Sten O. Nilsson Lill ₆ , Per-Ola Norrby ₇ , Antonio Ramirez ₈ , Edward C. Sherer ₁ , Jason Mustakis ₂ , Gerald J. Tanoury ₉

Affiliation

Computational and Structural Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
Small Molecule Design and Development, Eli Lilly and Company, Bangalore 560103, India
Molecular Design, Data and Computational Sciences, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States
Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46221, United States
Early Product Development and Manufacturing, Pharmaceutical Sciences, R&D, AstraZeneca Gothenburg, Mölndal 431 50, Sweden
Data Science & Modelling, Pharmaceutical Sciences, R&D, AstraZeneca Gothenburg, Mölndal 431 50 Sweden
Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States
Process Chemistry, Vertex Pharmaceuticals, 50 Northern Avenue, Boston, Massachusetts 02210, United States

将计算方法应用于理解和预测用于药物发现的类似物的性质已有很长的成功历史。然而，药物开发领域（候选后的选择）目前正在这个领域快速发展。由于计算硬件开发方面的革命和改进的计算技术，量子化学（QC）计算已成为该领域的重要工具，可以使复杂计算的结果为化学开发工作提供参考。结果，许多制药公司将质量控制作为药物开发工作流程的一部分。计算涵盖了过渡态计算，反应路径确定和势能表面扫描等范围。通过提供对化学过程的深入了解以及对潜在过程路线和条件的结果的预测性洞察力，可以实现这种快速增长的影响。这篇综述调查了制药行业中这些药物开发应用的最新技术。介绍了过去14年（2005-2019年）内出版物的计算方法，软件和其他指标的统计数据。描述了量子化学在反应优化和催化剂设计中影响实验的预测应用。讨论了硬件和软件功能上需要解决的重要缺陷，以使量子化学成为药物开发中更实用，更具影响力的工具。

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Applications of Quantum Chemistry in Pharmaceutical Process Development: Current State and Opportunities

Application of computational methods to understanding and predicting properties of analogues for drug discovery has enjoyed a long history of success. However, the drug development space (post-candidate selection) is currently experiencing a rapid growth in this arena. Due to the revolution in computing hardware development and improved computational techniques, quantum chemical (QC) calculations have become an essential tool in this space, allowing results from complex calculations to inform chemical development efforts. As a result, numerous pharmaceutical companies are employing QC as part of their drug development workflow. Calculations cover the range of transition state calculations, reaction path determination, and potential energy surface scans, among others. The impact of this rapid growth is realized by providing an in-depth understanding of chemical processes and predictive insight into the outcome of potential process routes and conditions. This review surveys the state of the art in these drug development applications in the pharmaceutical industry. Statistics of computational methods, software, and other metrics for publications in the last 14 years (2005–2019) are presented. Predictive applications of quantum chemistry for influencing experiments in reaction optimization and catalyst design are described. Important gaps in hardware and software capabilities that need to be addressed in order for quantum chemistry to become a more practical and impactful tool in pharmaceutical drug development are discussed. Perspectives for the future direction of application of QC to pharmaceutical drug development are proposed.

更新日期：2020-08-21

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