4.7 Article

Potential Energy Function for Fentanyl-Based Opioid Pain Killers

期刊

JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 60, 期 7, 页码 3566-3576

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.0c00185

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资金

  1. Excellence Initiative of the German Federal and State Governments via the Freie Universitat Berlin (FU)
  2. Center for Research Strategy of the FU
  3. Charite 3R | Replace -Reduce -Refine
  4. Deutsche Forschungsgemeinschaft [STE 477/19-1]
  5. Berlin Institute of Health (SPARK Validation Fund 2019 - Track 2)
  6. Slovenian Ministry of Science and Education [C3330-19-952021]
  7. Slovenian Research Agency programme [P2-0046, J1-6736]
  8. Slovenian Research Agency [L7-8269]

向作者/读者索取更多资源

Opioids are molecules whose binding to specialized G-Protein Coupled Receptors (GPCRs) triggers a signaling cascade that leads to the downregulation of pain pathways. Binding of an opioid to the membrane-embedded GPCR occurs when the opioid molecule is protonated, which provides a potential strategy to design nontoxic opioids that are protonated and bind to the GPCR only at the low pH of injured or inflamed tissue. Excellent model systems to study protonation-dependent binding of opioids to GPCRs are fentanyl, which is protonated and binds to the GPCR at both physiological and low pH, and the fluorinated fentanyl derivative NFEPP, which is protonated and binds to the GPCR only at low pH. The molecular mechanisms of fentanyl and NFEPP binding to the GPCR are largely unknown. To enable atomistic studies of opioid binding to GPCRs, we have carried out extensive quantum mechanical and classical mechanical computations to derive a potential energy function for fentanyl and NFEPP and present force field parameters for both opioid molecules. We find that fluorination alters the electronic ground state properties of fentanyl. As a consequence, fentanyl and NFEPP have distinct torsional and electrostatic properties likely to impact how they bind to receptors.

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