Molecular Modeling, Design, and Synthesis of Less Lipophilic Derivatives of 3-(4-Tetradecyloxybenzyl)-4H-1,2,4-oxadiazol-5-one (PMS1062) Specific for Group II Enzyme†

3-(4-Tetradecyloxybenzyl)-4H-1,2,4-oxadiazol-5-one (PMS1062 or I) can probably act as a PLA2-II inhibitor on the acute inflammation model, but its highly lipophilic character could prevent it from being biodistributed effectively. In this work, based on a molecular modeling study, we have proposed a model that may provide compounds retaining both anti-PLA2 activity and specificity while becoming active per os. Moreover, molecular dynamics and energy minimization enabled us to characterize the lowest-energy complexes of each derivative. Energy balances taking account of the conformational energy changes of both partners, along with the drug–protein interaction, were performed, and were further completed by single-point computations of the contributions of solvation/desolvation to the binding. The ordering of the resulting energy balances was found to be fully consistent with the experimentally ascertained ordering of affinities inferred from the IC50 values. The essential role of an indole group partaking in cation–π and hydrophobic interactions, together with the CaII-chelating oxadiazolone ring, was highlighted for the best binding compound. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)