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Design of first in class bitopic ligands targeting the sodium binding pocket in opioid receptors
Author(s) -
Faouzi Abdelfattah,
Zaidi Saheem,
Che Tao,
Kormos Chad,
Zhang Tiffany,
Madasu Manish,
Eans Shainnel,
Simons Chloe,
Pan Ying-Xian,
McLaughlin Jay,
Carroll Ivy,
Hassani Ream Al,
Roth Bryan,
Katritch Vsevolod,
Majumdar Susruta
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02437
Subject(s) - allosteric regulation , functional selectivity , g protein coupled receptor , receptor , chemistry , allosteric modulator , opioid , binding site , pharmacology , biology , biochemistry
Opioid agonists have been used in the field of pain management for centuries, but are considered a major public health concern, especially in the US. One of the biggest challenges consists in understanding the ability to target specifically the different subtypes of opioid receptors and to trigger a specific functional response correlating with an in vivo analgesic response devoid of side‐effects. These opioid receptors are part of the GPCRs family, which is known to have common features across different subfamilies. One important feature of these receptors is the presence of allosteric binding pockets, which is progressively gaining momentum as a novel target for current therapeutic strategies. We hypothesized that targeting an allosteric site could potentially allow for receptor functional selectivity, helping to reduce the overall side effects profile. One site, in particular, known as the Na + binding pocket, is known to play a key role in GPCR function and is thought to be the center of the functional mechanism, with several bias switches characterized in the pocket residues (Katritch et al ., Trends Biochem Sci . 2014). Here we report structure‐based rational drug design of bitopic ligands targeting the Na + pocket of mu (MOR) and kappa opioid receptors (KOR). Our designed bitopics show high affinity, subtype selectivity, G‐protein bias and analgesic actions in mice. Mutations in Na + binding pocket diminished functional potency validating allosteric site targeting. Together, results suggest the possibility of achieving subtype selectivity and identification of an additional subpocket in both MOR and KOR to reduce βarrestin‐2 recruitment by targeting an allosteric pocket in the opioid receptors. The highly conserved constitution of the Na + binding pocket opens the opportunity for rational discovery of new GPCR modulators with desired functional, and potentially therapeutic profile for opioids as well as other class A GPCRs. Support or Funding Information We gratefully acknowledge the financial support from Faculty Research Incentive Fund, NIDA, NIAAA and US department of defense. We also would like to thank the Philippe Foundation for their financial support.