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.
Highlights
Despite major efforts from the pharmaceutical industry, effective therapies for many central nervous system (CNS) diseases are still lacking.[1,2] A common property of CNS drugs is that these compounds interact with multiple targets and that this is essential for their therapeutic effect.[3,4] The fact that multi-target profiles may be required for treatment of complex diseases contrasts with the philosophy of modern drug discovery, which focuses on ligands with selectivity for a single target
The binding sites of the A2A adenosine receptor (A2AAR) and D2R were first inspected to assess strategies to design dual-target ligands of these two G-protein-coupled receptors (GPCRs)
One out of 12 residues, the GPCR family-conserved Trp6.48 (BallesterosWeinstein residue numbering scheme is shown as superscripts[22]), was the same in both sites and key residues for ligand recognition (A2AAR/Asn2536.55 and D2R/Asp1143.32) were different.[19,23]
Summary
Despite major efforts from the pharmaceutical industry, effective therapies for many central nervous system (CNS) diseases are still lacking.[1,2] A common property of CNS drugs (e.g. antipsychotics) is that these compounds interact with multiple targets and that this is essential for their therapeutic effect.[3,4] The fact that multi-target profiles may be required for treatment of complex diseases contrasts with the philosophy of modern drug discovery, which focuses on ligands with selectivity for a single target. Long-term use of l-DOPA leads to a gradual loss of drug efficacy and side effects such as motor fluctuations and dyskinesia.[1] An attractive alternative to targeting only the dopamine receptors is to consider the network of G-protein-coupled receptors (GPCRs) in the basal ganglia controlling movement, which includes the A2A adenosine receptor.[12] A compound with the ability to interact with both the A2A adenosine receptor (A2AAR) and the D2 dopamine receptor (D2R) could delay progression of the disease and treat the symptoms. Angewandte Chemie International Edition published by Wiley-VCH GmbH. Our results suggest a general strategy to design dualtarget ligands of GPCRs
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