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

Abstract

Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi‐target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure‐based strategy to identify dual‐target ligands of G‐protein‐coupled receptors is presented. We use this approach to design compounds that both antagonize the A2A adenosine receptor and activate the D2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure‐based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual‐target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.

Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter

“…To investigate these questions, we sought compounds with effects on SERT akin to ibogaine but acting with greater selectivity. Structure-based docking of large chemical libraries has driven discovery of novel compounds that have high affinity and selectivity for several families of biological targets (Alon et al, 2021;Ballante et al, 2021;Bender et al, 2021;Gabrielsen et al, 2012;Gabrielsen et al, 2013;Gunera et al, 2020;Kampen et al, 2021;Katritch et al, 2012;Kolb et al, 2009a;Kolb and Irwin, 2009;Kufareva et al, 2012;Kufareva et al, 2017;Kufareva et al, 2014;Manglik et al, 2016;Ngo et al, 2016;Orry et al, 2006;Ortiz Zacarías et al, 2021;Patel et al, 2020;Rognan, 2012;2017;Roth et al, 2017;Sadybekov et al, 2020;Scharf et al, 2019;Stauch et al, 2019;Stein et al, 2020;Uprety et al, 2021;Weiss et al, 2013;Wisler et al, 2018), though rarely transporters. We used the cryo-EM structure of SERT complexed with ibogaine in an inward-open conformation (Coleman et al, 2019) (PDB ID: 6DZZ) to computationally dock a library of 200 million make-on-demand molecules (Alon et al, 2021;Lyu et al, 2019;Sadybekov et al, 2022;Stein et al, 2020).…”