A comparative QSAR on 1,2,5-thiadiazolidin-3-one 1,1-dioxide compounds as selective inhibitors of human serine proteinases

Selective inhibitors of target serine proteinases have a potential therapeutic role for the treatment of various inflammatory and related diseases. We develop a comparative quantitative structure–activity relationships based analysis on compounds embodying the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. By means of classical Molecular Dynamics we obtain the conformation of each lowest-energy molecular structure from which we derive more than a thousand of structural descriptors necessary for building predictive QSAR models. We resort to two different modeling approaches with the purpose of testing the consistency of our results: (a) multivariable linear regressions based on the replacement method and forward stepwise regression, and (b) the calculation of flexible descriptors with the CORAL program. All the models are properly validated by means of standard procedures. The resulting QSAR models are supposed to be of great utility for the rational search and design (including synthesis and/or in vitro biochemical studies) of new effective non-peptidyl inhibitors of serine proteinases.

Dragon, Recon, and Coral molecular descriptors for a linear QSAR analysis on 1,2,5-thiadiazolidin-3-one 1,1-dioxide compounds as selective inhibitors of human serine proteinases.Figure optionsDownload high-quality image (73 K)Download as PowerPoint slideHighlights
► Development of QSAR models for predicting inhibitory activities on human serine proteinases HLE, Cat G and PR 3.
► Rational search of new inhibitors with the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold having low molecular weights.
► Validation of the QSAR models with external test sets, Y-randomization and cross-validation techniques.