Objective

In a previous study [1] it was shown that the human extracellular calcium-sensing receptor (hCaSR) plays a fundamental pathophysiological role in the context of allergic asthma. Therefore, the inhibition of hCaSR with calcilytics could break the pathological cycle which promotes airway hyperresponsiveness and inflammation within airway smooth muscle cells. For the evaluation of potential candidates, a homology model of hCaSR’s 7 transmembrane domain was created based on the metabotropic glutamate receptor 1 (mGlu1). The validation of the model revealed that the calcilytics bind to the postulated residues within the binding pocket of hCaSR according to mutagenesis studies [2]. Further docking experiments showed that the predicted pK values of known calcilytics highly correlate with the experimentally determined ones (R² = 0,85). The screening procedure is done with SAFAN-ISP. It is an innovative small molecule fragment approach which is suitable for in-silico profiling, drug repurposing, and side effect prediction. Preliminary screening with SAFAN-ISP resulted in 644 potential candidates out of over 11000 maximum diverse compounds.

[1] Sci Transl Med.2015 Apr 22;7(284):284ra60.

[2] Am J Physiol Lung Cell Mol Physiol.2016 Dec 1;311(6):L1113-L1140.