Combinatorial chemistry and library design have been reconciled by applying simple medicinal chemistry concepts to virtual library design. The herein reported "Scaffold-Linker-Functional Group" (SLF) approach has the aim to maximize diversity while minimizing the size of a scaffold-focused library with the aid of simple molecular variations in order to identify critical pharmacophoric elements. Straightforward rules define the way of assembling three building blocks: a conserved scaffold, a variable linker, and a variable functional group. By carefully selecting a limited number of functional groups not overlapping in pharmacophoric space, the size of the library is kept to a few hundred. As an application of the SLF approach, a small-sized combinatorial library (320 compounds) was derived from the scaffold of the known phosphodiesterase 4 inhibitor zardaverine. The most interesting analogues were further prioritized for synthesis and enzyme inhibition by FlexX docking to the X-ray structure of the enzyme, leading to a 900-fold increased affinity within nine synthesized compounds and a single screening round.