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  1. Article ; Online: PL-PatchSurfer: a novel molecular local surface-based method for exploring protein-ligand interactions.

    Hu, Bingjie / Zhu, Xiaolei / Monroe, Lyman / Bures, Mark G / Kihara, Daisuke

    International journal of molecular sciences

    2014  Volume 15, Issue 9, Page(s) 15122–15145

    Abstract: Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand ... ...

    Abstract Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer). PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD). We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets.
    MeSH term(s) Algorithms ; Binding Sites ; Ligands ; Molecular Docking Simulation/methods ; Protein Binding ; Proteins/chemistry ; Proteins/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
    Chemical Substances Ligands ; Proteins ; Small Molecule Libraries
    Language English
    Publishing date 2014-08-27
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms150915122
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  2. Article ; Online: Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.

    Thal, David M / Sun, Bingfa / Feng, Dan / Nawaratne, Vindhya / Leach, Katie / Felder, Christian C / Bures, Mark G / Evans, David A / Weis, William I / Bachhawat, Priti / Kobilka, Tong Sun / Sexton, Patrick M / Kobilka, Brian K / Christopoulos, Arthur

    Nature

    2016  Volume 531, Issue 7594, Page(s) 335–340

    Abstract: Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for ... ...

    Abstract Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.
    MeSH term(s) Acetylcholine/metabolism ; Allosteric Regulation/drug effects ; Allosteric Site/drug effects ; Alzheimer Disease ; Crystallization ; Crystallography, X-Ray ; Drug Inverse Agonism ; Humans ; Models, Molecular ; Nicotinic Acids/metabolism ; Nicotinic Acids/pharmacology ; Receptor, Muscarinic M1/chemistry ; Receptor, Muscarinic M1/metabolism ; Receptor, Muscarinic M4/chemistry ; Receptor, Muscarinic M4/metabolism ; Schizophrenia ; Static Electricity ; Substrate Specificity ; Surface Properties ; Thiophenes/metabolism ; Thiophenes/pharmacology ; Tiotropium Bromide/pharmacology
    Chemical Substances 3-amino-5-chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamide ; Nicotinic Acids ; Receptor, Muscarinic M1 ; Receptor, Muscarinic M4 ; Thiophenes ; Acetylcholine (N9YNS0M02X) ; Tiotropium Bromide (XX112XZP0J)
    Language English
    Publishing date 2016-03-17
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature17188
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  3. Article ; Online: Synthesis and pharmacological characterization of 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: identification of new potent and selective metabotropic glutamate 2/3 receptor agonists.

    Monn, James A / Valli, Matthew J / Massey, Steven M / Hao, Junliang / Reinhard, Matthew R / Bures, Mark G / Heinz, Beverly A / Wang, Xushan / Carter, Joan H / Getman, Brian G / Stephenson, Gregory A / Herin, Marc / Catlow, John T / Swanson, Steven / Johnson, Bryan G / McKinzie, David L / Henry, Steven S

    Journal of medicinal chemistry

    2013  Volume 56, Issue 11, Page(s) 4442–4455

    Abstract: As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent ...

    Abstract As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the α-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo.
    MeSH term(s) Administration, Oral ; Amino Acids, Dicarboxylic/chemical synthesis ; Amino Acids, Dicarboxylic/pharmacokinetics ; Amino Acids, Dicarboxylic/pharmacology ; Animals ; Antipsychotic Agents/chemical synthesis ; Antipsychotic Agents/pharmacokinetics ; Antipsychotic Agents/pharmacology ; Bridged Bicyclo Compounds/chemical synthesis ; Bridged Bicyclo Compounds/pharmacokinetics ; Bridged Bicyclo Compounds/pharmacology ; Cyclohexanes/chemical synthesis ; Cyclohexanes/pharmacokinetics ; Cyclohexanes/pharmacology ; Humans ; Male ; Models, Molecular ; Motor Activity/drug effects ; Psychotic Disorders/drug therapy ; Psychotic Disorders/psychology ; Rats ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/agonists ; Receptors, Metabotropic Glutamate/metabolism ; Stereoisomerism ; Structure-Activity Relationship
    Chemical Substances 2-amino-4-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid ; Amino Acids, Dicarboxylic ; Antipsychotic Agents ; Bridged Bicyclo Compounds ; Cyclohexanes ; Receptors, Metabotropic Glutamate ; metabotropic glutamate receptor 2 ; metabotropic glutamate receptor 3 ; eglumetad (ONU5A67T2S)
    Language English
    Publishing date 2013-06-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm4000165
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  4. Article ; Online: Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.

    Liu, Bin / Croy, Carrie H / Hitchcock, Stephen A / Allen, Jennifer R / Rao, Zhigang / Evans, David / Bures, Mark G / McKinzie, David L / Watt, Marla Leigh / Stuart Gregory, G / Hansen, Marvin M / Hoogestraat, Paul J / Jamison, James A / Okha-Mokube, Fese M / Stratford, Robert E / Turner, William / Bymaster, Frank / Felder, Christian C

    Bioorganic & medicinal chemistry letters

    2015  Volume 25, Issue 19, Page(s) 4158–4163

    Abstract: The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. ... ...

    Abstract The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
    MeSH term(s) Amides/chemical synthesis ; Amides/chemistry ; Amides/pharmacology ; Animals ; Dose-Response Relationship, Drug ; Drug Design ; Humans ; Molecular Structure ; Rats ; Receptor, Muscarinic M1/agonists ; Structure-Activity Relationship
    Chemical Substances Amides ; Receptor, Muscarinic M1
    Language English
    Publishing date 2015-10-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2015.08.011
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  5. Article ; Online: Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity.

    Chappell, Mark D / Li, Renhua / Smith, Stephon C / Dressman, Bruce A / Tromiczak, Eric G / Tripp, Allie E / Blanco, Maria-Jesus / Vetman, Tatiana / Quimby, Steven J / Matt, James / Britton, Thomas C / Fivush, Adam M / Schkeryantz, Jeffrey M / Mayhugh, Daniel / Erickson, Jon A / Bures, Mark G / Jaramillo, Carlos / Carpintero, Mercedes / Diego, José Eugenio de /
    Barberis, Mario / Garcia-Cerrada, Susana / Soriano, José F / Antonysamy, Stephen / Atwell, Shane / MacEwan, Iain / Condon, Bradley / Sougias, Christine / Wang, Jing / Zhang, Aiping / Conners, Kris / Groshong, Chris / Wasserman, Stephen R / Koss, John W / Witkin, Jeffrey M / Li, Xia / Overshiner, Carl / Wafford, Keith A / Seidel, Wesley / Wang, Xu-Shan / Heinz, Beverly A / Swanson, Steven / Catlow, John T / Bedwell, David W / Monn, James A / Mitch, Charles H / Ornstein, Paul L

    Journal of medicinal chemistry

    2016  Volume 59, Issue 24, Page(s) 10974–10993

    Abstract: As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 ( ... ...

    Abstract As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu
    MeSH term(s) Animals ; Antidepressive Agents/chemical synthesis ; Antidepressive Agents/chemistry ; Antidepressive Agents/pharmacology ; Behavior, Animal/drug effects ; Brain/drug effects ; Cyclohexanes/chemical synthesis ; Cyclohexanes/chemistry ; Cyclohexanes/pharmacology ; Dose-Response Relationship, Drug ; Drug Discovery ; Humans ; Male ; Mice ; Mice, Inbred Strains ; Models, Molecular ; Molecular Structure ; Motor Activity/drug effects ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Receptors, Metabotropic Glutamate/chemistry ; Receptors, Metabotropic Glutamate/isolation & purification ; Structure-Activity Relationship ; Swimming
    Chemical Substances 2-amino-3-((3,4-difluorophenyl)sulfanylmethyl)-4-hydroxy-bicyclo(3.1.0)hexane-2,6-dicarboxylic acid hydrochloride ; Antidepressive Agents ; Cyclohexanes ; Receptors, Metabotropic Glutamate ; metabotropic glutamate receptor 2 ; metabotropic glutamate receptor 3
    Language English
    Publishing date 2016-12-06
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.6b01119
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  6. Article: Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis.

    Petros, Andrew M / Dinges, Jurgen / Augeri, David J / Baumeister, Steven A / Betebenner, David A / Bures, Mark G / Elmore, Steven W / Hajduk, Philip J / Joseph, Mary K / Landis, Shelley K / Nettesheim, David G / Rosenberg, Saul H / Shen, Wang / Thomas, Sheela / Wang, Xilu / Zanze, Irini / Zhang, Haichao / Fesik, Stephen W

    Journal of medicinal chemistry

    2006  Volume 49, Issue 2, Page(s) 656–663

    Abstract: The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This ... ...

    Abstract The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-x(L) and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x(L) inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K(d)) of approximately 300 microM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x(L) with an inhibition constant (K(i)) of 36 +/- 2 nM.
    MeSH term(s) Aniline Compounds/chemical synthesis ; Aniline Compounds/chemistry ; Binding Sites ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Protein Binding ; Solubility ; Structure-Activity Relationship ; Sulfonamides/chemical synthesis ; Sulfonamides/chemistry ; bcl-X Protein/antagonists & inhibitors ; bcl-X Protein/chemistry
    Chemical Substances Aniline Compounds ; Ligands ; N-(4'-fluorobiphenyl-4-ylcarbonyl)-3-nitro-4-(2-phenylsulfanylethylamino)benzenesulfonamide ; Sulfonamides ; bcl-X Protein
    Language English
    Publishing date 2006-01-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm0507532
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