用藥物靶子的三維結構作為起點進行新藥分子的系統化設計。合理化藥物設計利用靶分子和其結合分子的高分辯率結構。合理化藥物設計對于了解分子活性的靶子（例如：酶）和結構修飾易于控制的分子效果最好。然而，用計算機模仿來創造、修飾和優化新藥只取得部分成功。一旦更多了解受體、配體的相互作用以及從對靶子在溶液中的特性的高分辯率研究中獲得更多的信息，人們就可以設計出更好的藥物。合理化藥物設計可以用于設計的組合文庫的建立，也就是：針對一個特殊受體增加發現先導復合物幾率所需的反應分子多樣性的文庫。

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.