VAMMPIRE-LORD (lead optimization by rational design) describes an innovative strategy to improve the binding affinity of a defined lead compound using 3D matched molecular pairs (3D-MMPs). 3D-MMPs are defined as pairs of molecules that differ in exactly one structural transformation and have a known bioactive conformation. We developed a novel atom-pair descriptor (LORD_FP) that represents the ligand-as well as the receptor environment-of a chemical transformation and built a predictive model based on 17602 3D-MMPs. We demonstrate that the created model is able to extrapolate the knowledge of a chemical transformation and the associated effect on ligand affinity to any similar system. VAMMPIRE-LORD was implemented as a web server that guides the user step-by-step through the optimization process of a defined lead compound.