4 years ago

Differentiating Physicochemical Properties between NDRIs and sNRIs Clinically Important for the Treatment of ADHD

Differentiating Physicochemical Properties between NDRIs and sNRIs Clinically Important for the Treatment of ADHD
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. Methods 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. Results 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. Conclusions The hydrophobic property of NDRI ADHD drugs' one functional group contributes to their selectivity when bind hNET and hDAT. General significance. 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.

Publisher URL: www.sciencedirect.com/science

DOI: S0304416517302398

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.