Differentiating physicochemical properties between NDRIs and sNRIs clinically important for the treatment of ADHD

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 11; pp. 2766 - 2777
• Main Authors: Wang, Panpan, Fu, Tingting, Zhang, Xiaoyu, Yang, Fengyuan, Zheng, Guoxun, Xue, Weiwei, Chen, Yuzong, Yao, Xiaojun, Zhu, Feng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2017
• Subjects: ADHD; aromatic compounds; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - metabolism; Attention Deficit Disorder with Hyperactivity - pathology; Binding mode; Dopamine - chemistry; Dopamine - metabolism; Dopamine Antagonists - administration & dosage; Dopamine Antagonists - chemistry; Gibbs free energy; Humans; hydrophobicity; moieties; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; molecular models; norepinephrine; Norepinephrine - antagonists & inhibitors; Norepinephrine - chemistry; Norepinephrine - metabolism; Norepinephrine-dopamine reuptake inhibitors; Selective norepinephrine reuptake inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors - administration & dosage; Serotonin and Noradrenaline Reuptake Inhibitors - chemistry; therapeutics; Molecular dynamics; Binding mode; ADHD; Norepinephrine-dopamine reuptake inhibitors; Selective norepinephrine reuptake inhibitors
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.07.022

Drugs available for treating attention-deficit hyperactivity disorder (ADHD) are mainly selective norepinephrine (sNRIs) and dual norepinephrine-dopamine (NDRIs) reuptake inhibitors. The major problem of sNRIs lines in their delayed onset of action and partial- or non-responses, which makes NDRIs distinguished in drug efficacy. Understanding of the differential binding modes of these 2 types of drugs to their corresponding targets can give great insights into the discovery of privileged drug-like scaffolds with improved efficacy. So far, no such study has been carried out. A combinatorial computational strategy, integrating homology modeling, molecular docking, molecular dynamics (MD) and binding free energy calculation, was employed to analyze the binding modes of 8 clinically important ADHD drugs in their targets. Binding modes of 2 types of ADHD drugs (sNRIs and NDRIs) in their targets was identified for the first time by MD simulation, and 15 hot spot residues were discovered as crucial for NDRIs' binding in hNET and hDAT. Comparing to sNRIs, a clear reduction in the hydrophobic property of NDRIs' one functional group was observed, and the depth of drugs' aromatic ring stretched into the pocket of both targets was further identified as key contributors to drugs' selectivity. The hydrophobic property of NDRI ADHD drugs' one functional group contributes to their selectivity when bind hNET and hDAT. These results provide insights into NDRI ADHD drugs' binding mechanisms, which could be utilized as structural blueprints for assessing and discovering more efficacious drugs for ADHD therapy. [Display omitted] •The shared binding mode of 2 types (sNRIs and NDRIs) of ADHD drugs to their targets (NET and DAT) is proposed.•The binding mode is interaction between 15 residues of targets and 3 functional groups of drugs.•The hydrophobicity of sNRIs' functional group contributes to their selectivity when bind hNET.