Δ13 LeuBAT-SNRI complexes

For the SNRI complexes with duloxetine and desvenlafaxine which locate at the primary binding pocket, amine group of duloxetine (figure 4a) forms a hydrogen bond with Asp24 while amine group of desvenlafaxine (figure 4b) forms no hydrogen bond with any residues. The naphthalene ring of duloxetine and the cyclohexanol ring from desvenlafaxine are sandwiched by hydrophobic groups Tyr21, Val104, Phe259 and Tyr108. The thiophene ring from duloxetine and the phenol ring from desvenlafaxine extend to the extracellular vestibule and interact with Phe253 by aromatic edge-to-face interactions (the most stable configuration with minima energy between two benzene rings). For hydroxyl group in the cyclohexanol of desvenlafaxine forms a hydrogen bond with the carbonyl group of Ser355 and the phenol hydroxyl interacts with Asp404 and Tyr107 by forming two hydrogen bonds. 

A

B

Figure 4. SNRIs in primary binding site of Δ13 LeuBAT. Transmembrane helixes TM1, TM3, TM6, TM8 and TM10 are shown in red, green, blue, yellow and magenta separately. The complexes are viewed from extracellular site with inhibitors shown as cyan sticks. Sodium ions and key residues are shown as purple star and orange sticks respectively.Hydrogen bonds, salt bridges and polar interactions are in dashed lines. (a) Duloxetine in the primary binding pocket of the D13 LeuBAT. (b) Desvenlafaxine  in the primary binding pocket of the D13 LeuBAT.

SNRIs:

duloxetine

desvenlafaxine