Quantitative structure-activity studies on H4 receptor antagonists

Abstract

Introduction:The drug development is considered as one of the most complex and costly process in pharmaceutical sciences. Application of computational techniques in this context can accelerate the identification of novel ligands by reduction of time and costs. One of the commonly used methods in this field is QSAR modeling, which investigates the relationship between the structural features of compounds and their biological activities. Among the histamine receptors, H4 receptor has gained much attention in recent years due to its significant role in inflammatory, allergic, and autoimmune diseases. There are several lines of evidence indicating therapeutic benefits of H4 receptor antagonists in treatment of such diseases.Objective:The objective of this study was to generate a reliable 3D-QSAR model for prediction of biological activity of H4 antagonists and investigation of key interactions between studied compounds and H4 receptor.Methods:In this study, alignment-independent 3D-QSAR modeling method was developed. A database consists of 77 compounds was collected from literature. Following the geometric optimization of the molecular structures using HyperChem program, QSAR modeling was carried out with Pentacle software. The obtained model was statistically evaluated for estimation of its predictive capability. Results:Statistical analysis of the data using PLS method showed that the final model had a correlation coefficient of R² equal to 0.84 and the internal and external validation correlation coefficients were 0.55 and 0.6, respectively. Moreover, Y-scrambling validation tests indicated the absence of chance correlation in the developed model.Conclusion:In this work, the most important features needed for antagonistic activity of triazine and pyrimidine derivatives were identified indicating importance of hydrogen bond and hydrophobic interactions in the complex of ligand-receptor. The results of this study can be used in designing of potent H4 antagonists where blockade of H4 receptors is required.