If drug properties are a function of its molecular structure, then the ideal drug candidate’s molecular structure is an inverse function of their maximum. This is the reasoning behind a drug discovery methodology presented in this work. As a model system, 45 sulfonamide derivatives in complex with carbonic anhydrase IX (CA IX) were used for development of strongly predictive quantitative structure-activity-lipophilicity relationships (QSALR) model. The model was reversed through numerical optimization in order to obtain an optimal molecular structure, in respect to a reference sulphonamide. Simultaneously, eight testing ligands were complexed with CA IX and characterized experimentally. Gel electrophoresis and MALDI-TOF/TOF-MS were used to determine the mass of the enzyme and explore the dimerization of CA IX. RP-LC and stopped-flow spectrophotometry were used for determination of lipophilicity and inhibitory activity, respectively. FTIR was used to elucidate the structural changes between the recombinant CA IX and its complexes. Molecular dynamics (MD) simulations were performed to complement the experiments, and vice-versa. Results have shown that upon simulation of acetazolamide in complex with CA IX, the system conserved the experimental flexibility profile, and the average radius of gyration obtained by MD analysis agreed well with its empirical value. MALDI-TOF-TOF/MS has confirmed strong binding of inhibitors to CA IX, while subtle weaker interactions between the ligands and CA IX were elucidated with spectroscopic experiments and MD analysis.