From Mathematics to Chemistry: A nontoxic pain killer designed by modeling of pathological receptor conformations

From Mathematics to Chemistry: A nontoxic pain killer designed by modeling of pathological receptor conformations

  • Datum: 15.09.2017
  • Uhrzeit: 13:00 - 14:00
  • Vortragende(r): Dr. Marcus Weber, Zuse-Institut Berlin (ZIB)
  • Numerical Mathematics Group
  • Ort: Max-Planck-Institut Magdeburg
  • Raum: Kleiner Seminarraum "Wiener"

From Mathematics to Chemistry: A nontoxic pain killer designed by modeling of pathological receptor conformations


Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide–binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine
> 3′,5′-monophosphate inhibition in vitro/./ It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.

Zur Redakteursansicht