Evaluation of Biological Activity and Computer‐Aided Design of New Soft Glucocorticoids

Abstract

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

Investigation of metabolic properties and effects of 17β‐carboxamide glucocorticoids on human peripheral blood leukocytes

“…Systemic side effects of these derivatives at their EC 50 values, evaluated on the basis of the thymus and spleen mass decreases after prolonged application (5 consecutive days), were lower than the effects of dexamethasone . In vitro estimation of skin permeability, which is important for their ability to reach dermis and systemic circulation, showed no significant differences among MPEA, BG, BEG, and dexamethasone . However, in silico prediction of MPEA metabolism and glucocorticoid receptor binding of its main metabolite indicate that metabolic degradation could be a reason for reduced systemic effects …”

“…In our previous study, local anti‐inflammatory activity of novel 17β‐carboxamide glucocorticoids was tested on rats using croton oil‐induced ear edema test and the results were evaluated after 4 h. Derivatives MPEA, BEG, and BG showed significant local anti‐inflammatory activity (higher maximal edema inhibition and lower EC 50 values in comparison to dexamethasone). Systemic side effects of these derivatives at their EC 50 values, evaluated on the basis of the thymus and spleen mass decreases after prolonged application (5 consecutive days), were lower than the effects of dexamethasone . In vitro estimation of skin permeability, which is important for their ability to reach dermis and systemic circulation, showed no significant differences among MPEA, BG, BEG, and dexamethasone .…”

“…Twenty‐two novel 17β‐carboxamide glucocorticoids have been recently synthesized in our laboratory and skin permeability and retention evaluated in vitro using PAMPA test and biopartitioning micellar chromatography . Anti‐inflammatory activity of these derivatives was tested in vivo using croton oil‐induced ear edema test, whereas systemic side effects were evaluated for those with the best local anti‐inflammatory activity (BG, BEG, and MPEA, Figure ).…”

“…Anti‐inflammatory activity of these derivatives was tested in vivo using croton oil‐induced ear edema test, whereas systemic side effects were evaluated for those with the best local anti‐inflammatory activity (BG, BEG, and MPEA, Figure ). Obtained results indicate that these compounds are potentially new soft glucocorticoids with fewer systemic side effects than the conventional glucocorticoid dexamethasone . However, mechanisms of their effects are not explained and their soft glucocorticoid nature has not been entirely proved yet.…”

Current computer-aided drug design methodologies in discovery of novel drug candidates for neuropsychiatric and inflammatory diseases

“…On the other hand, 3D-QSAR method focuses on the spatial properties of the compound, which may be crucial for distinguishing stereoisomers (55). Nevertheless, the representation of the molecular structure by calculated physicochemical and 3D structural descriptors is a critical step for the further model development for predicting small molecule-receptor interactions (56). Statistical methods are employed to select the most important molecular descriptors, as well as to gain further insights into the key structural features (53,54).…”