Editorial Cite This: J. Med. Chem. XXXX, XXX, XXX−XXX
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Allosteric Modulators of Drug Targets
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bound NAM ligands, Christopher, Keserű , and their colleagues analyze the contribution of hot spots and water networks to ligand−protein interactions in a study that provides important new insights into structure and function that together anticipate new strategies for the design of allosteric modulators. A Perspective article by Hall et al. summarizes positive allosteric modulators of the dopamine D1 receptor that are compared to orthosteric activators of the receptor. Two articles by Capuano and colleagues describe novel NAM scaffolds for the dopamine D2 receptor. In particular, subtle structural modifications to an indole-based chemotype were found to confer significant increases in both receptor affinity (>5000-fold) and cooperativity (100-fold) while affording a unique biochemical pharmacological profile that is quite distinct from earlier D2 receptor NAMs. A study by Zhou, Cunningham, and colleagues identifies a series of piperidinebased serotonin (5-HT) 5-HT2C receptor-selective PAMs that are proposed to bind to a topographically distinct allosteric site based upon ligand docking to the solved 5-HT2CR structure. These 5-HT2C NAMs are considered to have potential in the treatment of cocaine use disorder based on seminal in vivo studies conducted in rat models of cocaine self-administration. Manera et al. describe the discovery of the first synthetic cannabinoid receptor (CB) CB2R PAM, a pyridone derivative that displays antinociceptive activity in a mouse model of neuropathic pain. A contemporary overview of the arena of allosteric modulators of N-methyl-D-aspartate (NMDA) ionotropic receptors is provided by Monaghan et al., while Stadler and co-workers describe γ-aminobutyric acid type A receptor (GABAA) β2/3 subunit-selective PAMs that protect against pentylenetetrazole (PTZ)-induced seizures in vivo. A series of type I human α7 nicotinic acetylcholine receptor (α7 nAChR) PAMs that are selective over other nAChR subtypes, 5-HT3A, NMDA, and GABAA receptors and that exhibit good blood− brain barrier penetration is described by Li et al. A prototype α7 nAChR PAM from this series administered intraperitoneally to mice rescued the auditory gating deficit induced by an NMDA antagonist in a model of schizophrenia. Several articles profile allosteric modulators of enzymes, including inhibitors of a kinase, a tyrosine phosphatase, glutathione peroxidase 4, and both positive and negative modulators of proteasome activity. A Perspective article by Tsukamoto et al. summarizes recent progress in the design of allosteric inhibitors of kidney-type glutaminase, a multimeric enzyme that is upregulated in many glutamine-dependent cancer cells. The discovery of a potent, subtype-selective type III inhibitor of tropomyosin receptor kinase (TrkA) that binds to an allosteric pocket behind the ATP binding site of the enzyme is discussed by Bagal et al. Compound optimization relied upon a structure-based drug design approach and was focused on the identification of a peripherally restricted
llosteric modulation has emerged as a powerful approach for influencing protein function that can offer significant advantage over orthosteric modulation with respect to both selectivity and subtlety of effect as well as the physicochemical properties of a ligand, which may be orthogonal to those of the natural mediator. The advancement of technologies, including biological assay design, the development of computational models to predict mode of action, and ligand design platforms, has led to the discovery and characterization of allosteric modulators for a range of proteins, including G-proteincoupled receptors (GPCRs), ligand gated ion channels, enzymes, and many other drug targets. As a consequence, allosteric modulators of drug target proteins represent a rapidly evolving arena for the design of therapeutics that capitalizes upon the expertise of the medicinal chemistry community. This special issue of the Journal of Medicinal Chemistry is focused on “Allosteric Modulators of Drug Targets” and is part of a cross-thematic issue on “Allosteric Modulators” convened in collaboration with ACS Medicinal Chemistry Letters and ACS Chemical Neuroscience. This issue of the Journal captures several Perspectives and 17 regular articles that explore in depth the medicinal chemistry and biochemical pharmacology associated with a panoply of allosteric modulators that target a range of mechanistically distinct proteins. Most prominent are allosteric modulators of GPCRs, anchored by the Perspective articles by Zhang and Lu exploring drug−target interactions and Zhou et al., who summarize the field of allosteric modulation of class A GPCRs. Haskell-Luevano et al. report an innovative approach to the design of allosteric ligands for GPCRs that led to the characterization of the first biased modulator of melanocortin-4 (MC4R) receptor signaling, the elegance of which is synopsized in the Viewpoint by Sid Topiol (A Surprising Recipe for Designing Biased Ligands). The identification of allosteric modulators of the metabotropic glutamate receptor (mGlu) GPCR family has been an area of considerable focus over the past decade in an effort to identify selective ligands that are less polar than glutamate and its analogues and therefore offer sufficient CNS penetration to allow the testing of disease concepts in vivo. Several of the more recent discoveries are captured in articles in this special issue, with mGlu2 negative allosteric modulators (NAMs) described by Childress et al. while a team led by Szabo describes the identification of positive allosteric modulators (PAMs) of this receptor using a fragment-based optimization approach. Doornbos and colleagues describe the discovery and pharmacological characterization of the first covalent PAM of the mGlu2 receptor, a sulfonyl fluoride derivative that, based on mutagenesis and modeling studies, is hypothesized to react with threonine 791 of the protein. Studies by Bollinger et al. led to the development of a new benzo[d]isothiazole-based scaffold for the design of mGlu4 receptor PAMs that offers reduced CYP1A2 inhibition and an improved pharmacokinetic profile when compared to previously reported mGlu4 PAMs. Using X-ray crystal structures of the mGlu5 receptor with © XXXX American Chemical Society
Special Issue: Allosteric Modulators
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DOI: 10.1021/acs.jmedchem.8b01902 J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
Editorial
compound in order to allay safety concerns around inhibition of TrkA in the CNS. This culminated in the delivery of compound with high selectivity for TrkA over a broader kinome panel that was orally bioavailable and demonstrated efficacy in several rat models of pain. Tautermann et al. detail the discovery of the first small molecule allosteric activator of protein tyrosine phosphatase nonreceptor type 5 (PEPN5, STEP), a brain-specific enzyme that regulates synaptic function and plasticity by modulating NMDA receptor trafficking. A phenol-based phenethylamine prototype was discovered by fragment-based screening and optimized into a more potent ligand that was shown by 15N NMR and X-ray biophysical techniques to bind to the phosphatase domain. Using a combination of computational strategies and experimental studies, Li et al. report the discovery of allosteric activators of glutathione peroxidase 4 (GPX4) that suppress ferroptosis (a form of cell death that is nonapoptotic in mechanism and characterized by increased levels of lipid hydroperoxides), reduce proinflammatory lipid mediator production, and inhibit NF-κB pathway activation in a battery of in vitro, cell-based assays. Giżyńska et al. identify a series of proline- and argininerich peptides derived from PR11 that function as allosteric modulators of the 20S proteasome, either negative or positive dependent on structure, with a resolved X-ray cocrystal structure demonstrating that one of these inhibitors binds into a pocket that is remote from the active sites of the enzyme and utilized by natural enzyme regulators. Finally, in a Perspective article, Colombo et al. summarize recent developments in the design and profiling of allosteric modulators of heat shock proteins 70 (HSP70) and 90 (HSP90) that provide insight into the complex function of these important molecular chaperones and their potential as targets for therapeutic intervention. This timely special issue focused upon contemporary allosteric modulator discovery and development efforts contains contributions that are at the forefront of the medicinal chemistry field. The description of exciting advances and firstin-class molecule discoveries in the diverse collection of papers and Perspective articles that emanate from both academic and industrial scientists from around the world combine to provide a snapshot of the current state of allosteric modulator design and application. The guest editors are highly appreciative of all of the authors, reviewers, Journal of Medicinal Chemistry editors, and editorial staff for their hard work and efforts that contribute to the success of this special issue.
Carrie Haskell-Luevano, Associate Editor and Guest Editor University of Minnesota, United States
Nicholas A. Meanwell, Perspectives Editor
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Bristol-Myers Squibb Research and Development, United States
AUTHOR INFORMATION
ORCID
Carrie Haskell-Luevano: 0000-0002-6783-5972 Nicholas A. Meanwell: 0000-0002-8857-1515 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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DOI: 10.1021/acs.jmedchem.8b01902 J. Med. Chem. XXXX, XXX, XXX−XXX
