Interaction analyses of hTAAR1 and mTAAR1 with antagonist EPPTB.

Trace amine-associated receptor 1 (TAAR1) plays a critical role in regulating monoaminergic activity. EPPTB is the only known selective potent antagonist of the mouse (m) TAAR1 presently, while it was shown to be weak at antagonizing human (h) TAAR1. The lack of high-resolution structure of TAAR1 hinders the understanding of the differences in the interaction modes between EPPTB and m/hTARR1. The purpose of this study is to probe these interaction modes using homology modeling, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. Eight populated conformers of hTAAR1-EPPTB complex were observed during the MD simulations and could be used in structure-based virtual screening in future. The MM-GBSA binding energy of hTAAR1-EPPTB complex (-96.5 kcal/mol) is larger than that of mTAAR1-EPPTB complex (-106.7 kcal/mol), which is consistent with the experimental finding that EPPTB has weaker binding affinity to hTAAR1. The several residues in binding site of hTAAR1 (F154, T194 and I290) are different from these of mTAAR1 (Y153, A193 and Y287), which might contribute to the binding affinity difference. Our docking analysis on another hTAAR1 antagonist Compound 3 has found that: 1). this compound binds in different pockets of our mTAAR1 and hTAAR1 homology models with a slightly stronger binding affinity to hTAAR1; 2). both antagonists bind to a very similar pocket of hTAAR1.