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

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.

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Extensive recent reviews have summarized the major developments in finding of new structures (agonists, partial agonists and antagonists), in vitro affinity and selectivity (versus D2R) of several D3R ligands [79,[111][112][113]]. An excellent review summarizing new lines in search for D2R/D3R drug research has recently been published [114]. Here, we point out some issues related to potency and selectivity and report on some most recent development in identification of selective agonists and antagonists.…”

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**

“…Other type of comparable ligands are designed to simultaneously bind two orthosteric sites of a (homo/hetero) GPCR dimer [16] . These type of ligands have been recently reviewed [17] …”

Structure‐Guided Design of G‐Protein‐Coupled Receptor Polypharmacology

“…Crystal structures of GPCRs have revealed druggable secondary binding pockets, which can be targeted either by allosteric or bitopic compounds. Bitopic (also termed dualsteric) ligands that extend into secondary binding pockets have primarily been used to attain subtype selectivity and biased signalling [25, 26, 44] . Here, we demonstrate that such compounds can also be used to design polypharmacology.…”

“…Many class A GPCRs have secondary binding pockets, which are formed by the extracellular entrance to the orthosteric site. Secondary pockets are targets of allosteric modulators and subtype selective ligands can be obtained by forming interactions in these less conserved regions [25, 26] . We hypothesized that the secondary binding pockets could also be targeted to achieve polypharmacology and analysed these sites in both receptors.…”

“…For disparate targets, one possible strategy is to design bivalent compounds, which consist of two single‐target ligands connected by a linker. Although these are useful as chemical probes to study GPCR dimers, [25, 42, 43] this approach often leads to compounds with high molecular weight that are unlikely to possess drug‐like properties and cross the blood–brain barrier. Structure‐based modelling provides an additional route to design drugs with multi‐target profiles.…”