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) stu dy using the comparative molecular field analysis (CoMFA) method was perfor med on a series of interleukin 1-beta converting enzyme (ICE) inhibitors. T he 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 wer e modeled using the X-ray crystal structure of tetrapeptide aldehyde inhibi tor/ICE complex. The inhibitor compounds were considered both as neutral sp ecies and as P1 carboxylate ionized species. Superimpositions were performe d using two alignment rules, namely, an alignment of the structures based o n RMS fitting of the backbone heavy atoms of each structure to compound 2 a nd 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 L UMO energies or ClogP as additional descriptors in the QSAR table did not i mprove the significance of the CoMFA models. Steric and electrostatic field s of the inhibitors were found to be the relevant descriptors for structure -activity relationships. The predictive ability of the CoMFA model was eval uated by using a test set of 10 compounds (r(pred)(2) as high as 0.859). Fu rther comparison of the coefficient contour maps with the steric and electr ostatic properties of the receptor show a high level of compatibility.