用药物靶子的三维结构作为起点进行新药分子的系统化设计。合理化药物设计利用靶分子和其结合分子的高分辩率结构。合理化药物设计对于了解分子活性的靶子（例如：酶）和结构修饰易于控制的分子效果最好。然而，用计算机模仿来创造、修饰和优化新药只取得部分成功。一旦更多了解受体、配体的相互作用以及从对靶子在溶液中的特性的高分辩率研究中获得更多的信息，人们就可以设计出更好的药物。合理化药物设计可以用于设计的组合文库的建立，也就是：针对一个特殊受体增加发现先导复合物几率所需的反应分子多样性的文库。

The systematic design of new drug molecules using the three-dimensional structure of the drug target as a starting point. Rational drug design (also known as structure-based drug design) uses the high-resolution (atomic) structure of the target molecule, and of molecules that bind to it. Rational drug design has worked best for targets where the molecular mechanism of their activation or inactivation is well understood (such as enzymes); and for molecules where structural modifications are readily engineered (such as antibodies). However, the use of computer simulations to create, modify and optimize new drugs from scratch has as yet had only mixed success; better drugs will be designed once more is understood about receptor-ligand interactions and more information about targets is available from high-resolution studies of their properties in solution. Rational drug design has found its application in the creation of "designed" combinatorial libraries, i.e. libraries built to reflect the molecular diversity needed to optimize the likelihood of discovering lead compounds against a particular receptor.