Molecular modeling studies of 2-substituted cephalosporin esters binding to human leukocyte elastase

A series of 17 putative human leukocyte elastase (HLE) inhibitors belonging to the family of cephalosporin esters have been studied by means of molecular modeling techniques. The optimized conformation (molecular mechanics) of HLE was used as input for a series of simulated annealing calculations meant to locate a lower energy minimum than that identified by the previous minimization. Manual and automated docking experiments with all the 17 compounds have then been made with elastase in the lowest energy conformation found by the annealing phase. Further molecular dynamics studies of the complexes made by the enzyme with two different inhibitors, as well as a relative free-energy calculation of the two above-mentioned complexes, have been performed in order to get information about the recognition/binding process. The relationships between the steric, electrostatic and lipophilic descriptors (some of which were obtained with semiempirical MO calculations) of the inhibitors, their intermolecular non-bond interaction energies (INIs) and their IC50s have been described with a series of statistical equations. PLS and MLR-like models explaining such relationships have been generated.