NK1 receptor binding of a few low molecular weight 3,5-bistrifluoromethylbenzene derivatives

We were interested in finding smallest possible ligands of the NK1 receptor (NK1R). Based on structural considerations and molecular docking (scoring) we selected six simple (low molecular weight, MW) 3,5-bistrifluoromethylbenzene derivatives and tested them for human NK1R affinity. The compounds turned out to have detectable but very low affinity for the receptor (IC50 > 100 μM). The discrepancy between the docking scores and the experimental affinity provoked us to perform additional tests of AutoDock Vina scoring function performance against NK1R. The scoring function did not differentiate low MW-low affinity from low MW-high affinity binders, while it underestimated affinity of low MW-high affinity in comparison to high MW-high affinity compounds. The scoring function did not achieve satisfactory performance in discerning low MW-low affinity and low MW-high affinity binders from the sets of decoys. Analysis of molecular dynamics simulation of one of the studied compounds with NK1R suggests that docking might overestimate strength of the H-bond interaction.