Fattori Daniela
Menarini Ricerche S.p.A., Chemistry Departmen,t Via Tito Speri 10, I-00040 Pomezia, Rome, Italy.
Drug Discov Today. 2004 Mar 1;9(5):229-38. doi: 10.1016/S1359-6446(03)03007-1.
The successful practice of medicinal chemistry is crucially dependent on the principles of molecular recognition: the first and "fundamental" requirement for a drug is to bind to its target; specificity, or at least selectivity, of binding is also a must. Subsequent optimization steps to develop a lead compound into a drug are a complex mixture of processes that are not yet fully understood or predictable. Fortunately, criteria exist to discard leads that would be intractable for optimization. The concepts of non-lead-likeness and lead-likeness, in respect to drug-likeness and non-drug-likeness, have prompted a rich discussion in the recent medicinal chemistry literature. The fragment approach is an emerging philosophy in the process of lead compound discovery. The basic interactions responsible for binding affinity are defined from the "protein interactions world" and key structural fragments are combined according to the criteria of three-dimensional diversity to find new leads. New techniques in screening are used for the detection of the weaker interactions of fragments with their targets that might be undetectable in classical biological assays.
药物的首要且“根本”要求是与靶点结合；结合的特异性或至少是选择性也是必不可少的。将先导化合物开发成药物的后续优化步骤是一系列复杂的过程，目前尚未完全理解或预测。幸运的是，存在一些标准来舍弃那些难以优化的先导物。关于类药物性和非类药物性，非先导物样性和先导物样性的概念在近期的药物化学文献中引发了热烈讨论。片段方法是先导化合物发现过程中一种新兴的理念。负责结合亲和力的基本相互作用是从“蛋白质相互作用领域”定义的，关键结构片段根据三维多样性标准进行组合以寻找新的先导物。筛选中的新技术用于检测片段与其靶点之间较弱的相互作用，这些相互作用在经典生物学检测中可能无法检测到。
