Pyridopyrazine derivatives as highly selective histamine H4 receptor antagonist for the treatment of atopic dermatitis: QSAR modeling and molecular docking studies

Abstract

<p>Atopic dermatitis (AD) is a prevalent inflammatory skin condition, primarily characterized by intense pruritus and chronic inflammation. Current therapeutic options targeting the histamine H4 receptor (H4R) have shown limited efficacy in addressing both pruritus and inflammation comprehensively. This study investigates pyridopyrazine derivatives as potential H4R antagonists with a focus on their suitability for AD treatment. To evaluate these compounds, we applied quantitative structure–activity relationship (QSAR) models and molecular docking techniques. A set of 33 pyridopyrazine derivatives was analyzed using principal component regression (PCR), multiple linear regression (MLR), and partial least squares (PLS) methodologies. Molecular descriptors were computed, and collinearity among descriptors was assessed through principal component analysis (PCA). Model performance was evaluated using the root mean square error (RMSE) and coefficient of determination (R<sup>2</sup>) values, providing insight into predictive accuracy. The PCR model emerged with strong predictive capabilities, showing an RMSE of 1.017 and an R<sup>2</sup> of 0.897. Furthermore, molecular docking results indicated potent binding interactions with H4R, primarily through hydrophobic and hydrogen-bonding interactions. Notably, compound C11 demonstrated the highest binding affinity, underscoring its potential as a valuable candidate for anti-inflammatory development. In conclusion, pyridopyrazine derivatives, particularly compound C11, exhibit promising anti-inflammatory properties with specific binding efficacy to H4R, suggesting potential for advancing AD treatment options.</p>