Docking calculations that allow the estimation of the binding energy of small ligands in the GIIA sPLA(2) active site were used in a structure-based design protocol. Four GIIA sPLA(2) inhibitors co-crystallised with the enzyme, were used for examining the enzyme active site and for testing the FlexX in SYBYL® 6.8 molecular docking program to reproduce the crystallographic experimental data. The FPL67047XX inhibitor was chosen as a prototype structure for applying free energy perturbation (FEP) studies. Structural modifications of the initial structure of the FPL67047XX inhibitor (IC50 0.013 µM) were performed in an effort to optimise the interactions in the GIIA sPLA(2) active site. The structural modifications were based on: (1) the exploration of absolute configuration (i.e. comparison of the binding score of (R)- and (S)-enantiomers); (2) bioisosterism (i.e. replacement of the carboxylate group with the bioisosteric sulphonate and phosphonate groups); (3) insertion of substituents that fit better in the active site. The generated new structures exhibited higher binding energy. Such structures may spark off the interest of medicinal chemists for synthesizing potentially more active GIIA sPLA(2) inhibitors.
February 1, 2010