Three-dimensional quantitative structure-activity relationship of interleukin 1-beta converting enzyme inhibitors: A comparative molecular field analysis study.

A three-dimensional quantitative structure-activity relationship (QSAR) study using the comparative molecular field analysis (CoMFA) method was performed on a series of interleukin 1-beta converting enzyme (ICE) inhibitors. The compounds studied have been reported to be time-dependent inhibitors of ICE. This study was performed using 49 compounds, in which the CoMFA models were developed using a training set of 39 compounds. All the compounds were modeled using the X-ray crystal structure of tetrapeptide aldehyde inhibitor/ICE complex. The inhibitor compounds were considered both as neutral species and as P1 carboxylate ionized species. Superimpositions were performed using two alignment rules, namely, an alignment of the structures based on RMS fitting of the backbone heavy atoms of each structure to compound 2 and an alignment based on SYBYL QSAR rigid body field fit of the steric and electrostatic fields of the molecules to the fields of compound 2. Use of LUMO energies or ClogP as additional descriptors in the QSAR table did not improve the significance of the CoMFA models. Steric and electrostatic fields of the inhibitors were found to be the relevant descriptors for structure-activity relationships. The predictive ability of the CoMFA model was evaluated by using a test set of 10 compounds (r2pred as high as 0.859). Further comparison of the coefficient contour maps with the steric and electrostatic properties of the receptor show a high level of compatibility.