Whittle P J, Blundell T L
Pfizer Central Research, Sandwich, Kent, United Kingdom.
Annu Rev Biophys Biomol Struct. 1994;23:349-75. doi: 10.1146/annurev.bb.23.060194.002025.
Design cycles will undoubtedly play an increasingly important role in drug discovery in the coming years, as the amount of structural information on protein targets continues to rise. However, the traditional method of drug discovery, based upon random screening and systematic modification of leads by medicinal chemistry techniques, will probably not be abandoned completely because it has a potentially important advantage over more structure-based methods--namely, leads identified in this way are unlikely to show a close resemblance to the natural ligand or substrate. They may, therefore, have advantages in terms of patent novelty, selectivity, or pharmacokinetic profile. However, such leads could then serve as the basis for structure-based, rational modification programs, in which their interactions with target receptors are defined (as we have described) and improved molecules are designed. A final important point to be made about structure-based design in drug discovery is that, while it can be of great use in the initial process of identifying ligands with improved affinity and selectivity in vitro, it can usually say very little about other essential aspects of the drug discovery process, e.g. the need to achieve an adequate pharmacokinetic profile and low toxicity in vivo. This observation reminds us that drug design is a multidisciplinary process, involving molecular biologists, biochemists, pharmacologists, organic chemists, crystallographers, and others. In order to be effective, therefore, structure-based design must be properly integrated into the overall discovery effort.
随着蛋白质靶点结构信息的不断增加，设计循环在未来几年的药物发现中无疑将发挥越来越重要的作用。然而，基于随机筛选和通过药物化学技术对先导化合物进行系统修饰的传统药物发现方法可能不会被完全摒弃，因为它相对于更多基于结构的方法具有潜在的重要优势——即，以这种方式鉴定出的先导化合物不太可能与天然配体或底物有密切的相似性。因此，它们在专利新颖性、选择性或药代动力学特征方面可能具有优势。然而，这些先导化合物随后可作为基于结构的合理修饰计划的基础，在该计划中确定它们与靶受体的相互作用（如我们所描述的）并设计出改进的分子。关于药物发现中基于结构的设计，最后要指出的一个重要点是，虽然它在体外鉴定具有更高亲和力和选择性的配体的初始过程中可能非常有用，但它通常对药物发现过程的其他重要方面，例如在体内实现足够的药代动力学特征和低毒性的必要性，所说甚少。这一观察结果提醒我们，药物设计是一个多学科过程，涉及分子生物学家、生物化学家、药理学家、有机化学家、晶体学家等。因此，为了有效，基于结构的设计必须适当地融入到整体发现工作中。
