2016 Philip S. Portoghese Medicinal Chemistry Lectureship: Designing Bivalent or Bitopic Molecules for G-Protein Coupled Receptors. The Whole Is Greater Than the Sum of Its Parts

Amy Hauck Newman, Francisco O. Battiti, Alessandro Bonifazi

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

The genesis of designing bivalent or bitopic molecules that engender unique pharmacological properties began with Portoghese's work directed toward opioid receptors, in the early 1980s. This strategy has evolved as an attractive way to engineer highly selective compounds for targeted G-protein coupled receptors (GPCRs) with optimized efficacies and/or signaling bias. The emergence of X-ray crystal structures of many GPCRs and the identification of both orthosteric and allosteric binding sites have provided further guidance to ligand drug design that includes a primary pharmacophore (PP), a secondary pharmacophore (SP), and a linker between them. It is critical to note the synergistic relationship among all three of these components as they contribute to the overall interaction of these molecules with their receptor proteins and that strategically designed combinations have and will continue to provide the GPCR molecular tools of the future.

Original languageEnglish (US)
Pages (from-to)1779-1797
Number of pages19
JournalJournal of medicinal chemistry
Volume63
Issue number5
DOIs
StatePublished - Mar 12 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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