Abstract
Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.
Highlights
Selective norepinephrine reuptake inhibitors provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy
Multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs, and 3 lines of evidences were provided to verify the calculation results
A binding mode shared by approved sNRIs was discovered by clustering the binding free energies of residues
Summary
Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. Based on the X-ray crystal structure of hNET’s bacterial and invertebrate homologs[18,23, 7] residues (Phe[72], Asp[75], Val[148], Tyr[152], Phe[317], Phe[323], Ser420) were suggested as critical for some sNRIs (e.g. reboxetine) by visualizing the interaction distance between ligands and the target[23]. Computational methods have been proposed and frequently used to elaborate the binding mode between sNRIs and hNET with great efficiency and accuracy[28] These methods were applied (1) to elucidate binding mechanisms of substrates and inhibitors to monoamine transporter (MAT)[29,30,31,32,33,34,35,36] (2) to discover novel scaffolds of MAT inhibitors by virtual screening[37,38,39], and (3) to distinguish various molecular mechanisms of enantiomers binding to MAT40,41. There is an urgent need to reveal the mechanism underlying sNRIs’ pharmacodynamics and target recognition[23,25]
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