A series of monocarboxylated chalcones e g compounds and

A series of monocarboxylated chalcones (e.g. compounds 7 and 8, Fig. 2A) was previously identified as good CysLT1 antagonists [20], and none of them exhibited CysLT2 antagonistic activities (Supplementary Table S1). This study was consistent with reported result that CysLT2 Index Kit 1 was not sensitive to classical CysLT1 antagonists [21], [22]. A review of the structures of reported CysLT2 antagonists revealed several common features among CysLT2 antagonists that are concluded and highlighted as shown in Fig. 2B. Thus, two carboxyl groups were introduced onto the A-ring of chalcones and a lipophilic chain was introduced on the B-ring of chalcones to give dicarboxylated chalcones as potential CysLT2 antagonists (Fig. 2C). Herein, with the aim to enhance accuracy and efficiency in the development of novel CysLT2 antagonists, 3D structure of CysLT2 was constructed through homology modeling and dynamic simulations. The binding pocket of CysLT2 was defined and the interaction mode between CysLT2 and HAMI3379 was proposed. The newly designed dicarboxylated chalcones were then virtually evaluated by molecular docking and preferable screened hits 13a–f were synthesized and biologically evaluated for CysLT2 antagonistic activities.
Computational methods
Results and discussion
Conclusion The 3D structure of CysLT2 was established using homology modelling and applied in virtually evaluation of newly designed dicarboxylated chalcones using molecular docking. This approach led to the identification of six promising screened hits 13a–f, which were synthesized and biologically evaluated for CysLT2 antagonistic activities. The identification of compounds 13e and 13f with good and selective CysLT2 antagonistic activities indicated that combination of homology model and structure-based development of novel specific CysLT2 antagonists is a rational strategy. The interaction mode between CysLT2 and its ligands proposed in present study would be useful and valuable for further structural optimization of CysLT2 antagonists. To the best of our knowledge, the homology model of CysLT2 receptor and its application in structure-based lead optimization are reported for the first time. Also, the discovery of novel dicarboxylated chalcones, such as compounds 13e and 13f, as CysLT2 antagonists would be interesting leads to do further structure–activity exploration and structurally optimization.
Experimental
Acknowledgements The authors are grateful to the support provided by the National Natural Science Foundation of China (No. 81001359) and the China Postdoctoral Science Foundation (No. 201003734) and the Fundamental Research Funds for the Central Universities (No. 2011QNA7010).
Introduction Cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4, are inflammatory mediators derived from the 5-lipoxygenase pathway of arachidonic acid metabolism. As these mediators are known to be deeply involved in bronchial asthma via activation of the CysLT1 receptor,2, 3, 4 selective antagonists of this receptor, including pranlukast,5, 6 montelukast, and zafirlukast have widely been used as therapeutic agents for bronchial asthma. On the other hand, a number of studies have cloned and characterized another receptor subtype of CysLTs termed CysLT2 receptor.9, 10, 11 This receptor, like the CysLT1 receptor, is a G-protein-coupled receptor with an amino acid sequence 38% identical to that of the CysLT1 receptor. CysLT2 receptor mRNA has been detected in a number of human organ and tissues, including lung macrophages, airway smooth muscles, and peripheral blood leukocytes, and its expression has been identified on the mucus gland and nasal mucosal epithelium of patients with chronic rhinosinusitis, or allergic nasal vascular smooth muscles.13, 14 As for endogenous ligands binding, it is reported that CysLTs order of binding to human CysLT1 receptors is LTD4 > LTC4 = LTE4, while that for CysLT2 receptors is LTC4 = LTD4 > LTE4, Based on these findings, it is expected that the CysLT2 receptor is involved in the pathophysiology of bronchial asthma. However, it is unclear where CysLT2 receptors are histologically expressed in airway tissues of asthma subjects.