ABSTRACT
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.
Subject(s)
Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , Serine Proteases/chemistry , Serine Proteases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Drug Design , Humans , Linear Models , Molecular Conformation , Molecular Dynamics Simulation , Quantitative Structure-Activity RelationshipABSTRACT
Fibroblast-like synoviocytes (FLS) play a major role in the pathogenesis of rheumatoid arthritis (RA). FLS isolated from patients with RA (FLS-RA) express B cell-activating factor belonging to the TNF family (BAFF), a cytokine that has been associated with the onset and progression of RA. Glucocorticoids are powerful anti-inflammatory drugs used in the treatment of RA. In the present study, we examined the effect of dexamethasone (Dex) on constitutive and TNF-alpha- and IFN-gamma-induced BAFF expression in FLS-RA. BAFF mRNA expression and soluble BAFF were determined by RT-PCR and ELISA, respectively. The results showed that constitutive BAFF mRNA expression was inhibited by Dex in a dose- and time-dependent manner. Also, Dex inhibited the secretion of BAFF in a time-dependent manner reaching 76% of inhibition 72 h after treatment. Moreover, Dex suppressed both mRNA and protein BAFF expression induced by TNF-alpha but had no effect on IFN-gamma-induced BAFF expression. In comparison with B cells cultured alone, B cells co-cultured with FLS-RA exhibited a higher survival, which was inhibited when FLS-RA were pretreated with Dex. However, the enhanced B cell survival was reestablished by the addition of rhBAFF. Therefore, Dex is a potent inhibitor of constitutive and TNF-alpha-induced BAFF expression in FLS-RA.
