Scapin Giovanna
Department of Medicinal Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA.
Curr Pharm Des. 2006;12(17):2087-97. doi: 10.2174/138161206777585201.
In the past few years macromolecular crystallography has become a standard technique used by many pharmaceutical and biotechnology companies. This methodology offers details of protein-ligand interactions at levels of resolution virtually unmatched by any other technique, and this approach holds the promise of novel, more effective, safer and cheaper drugs. Although crystallography remains a laborious and rather expensive technique, remarkable advances in structure determination and structure based drug design (SBDD) have been made in recent years. This process has been aided by recent technological innovations such as high-throughput crystallization, high performance synchrotron beamlines, and new methods in structural bioinformatics and computational chemistry prompted by the structural genomics effort. As a consequence of the increased availability of structural data, the use of structure-based information has expanded from simple protein-ligand interaction analysis to include other aspects of the drug discovery process like target selection and initial lead discovery that used to be almost the exclusive property of biology and chemistry. This review will cover recent examples to illustrate how macromolecular crystallography has evolved and how structural information is now being used in the different stages of the drug discovery process. Advantages and shortcomings of the methodology will also be discussed.
在过去几年中，大分子晶体学已成为许多制药和生物技术公司使用的标准技术。这种方法能够在分辨率水平上提供蛋白质-配体相互作用的细节，几乎是其他任何技术都无法比拟的，并且这种方法有望开发出新颖、更有效、更安全且更便宜的药物。尽管晶体学仍然是一项费力且相当昂贵的技术，但近年来在结构测定和基于结构的药物设计（SBDD）方面已取得了显著进展。这一进程得益于近期的技术创新，如高通量结晶、高性能同步加速器光束线，以及结构基因组学研究推动的结构生物信息学和计算化学新方法。由于结构数据的可得性增加，基于结构的信息应用已从简单的蛋白质-配体相互作用分析扩展到包括药物发现过程的其他方面，如靶点选择和最初的先导化合物发现，而这些过去几乎完全属于生物学和化学领域。本综述将涵盖近期的实例，以说明大分子晶体学是如何发展的，以及结构信息如今在药物发现过程的不同阶段是如何被使用的。还将讨论该方法的优点和缺点。
