In Search of Allosteric Modulators of α7-nAChR by Solvent Density Guided Virtual Screening

被引:18
作者
Dey, Raja [1 ,2 ]
Chen, Lin [1 ,2 ,3 ]
机构
[1] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA
[2] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA
[3] Cent South Univ, Xiangya Hosp, Chinese Minist Hlth, Key Lab Canc Prote, Changsha 410008, Hunan, Peoples R China
关键词
Nicotinic acetylcholine receptor; Alpha; 7; Allosteric modulator; Virtual screening; Docking; NICOTINIC ACETYLCHOLINE-RECEPTORS; ALPHA-BUNGAROTOXIN; DRUG DESIGN; IN-VITRO; 4-(5-(4-CHLOROPHENYL)-2-METHYL-3-PROPIONYL-1H-PYRROL-1-YL)BENZENESULFONAMIDE A-867744; EXTRACELLULAR DOMAIN; MOLECULAR DOCKING; CRYSTAL-STRUCTURE; V3; LOOP; AGONIST;
D O I
10.1080/07391102.2011.10508600
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels whose activity can be modulated by endogenous neurotransmitters as well as by synthetic ligands that bind the same or distinct sites from the natural ligand. The subtype of alpha 7 nAChR has been considered as a potenial therapeutic target for Alzheimer's disease, schizophrenia and other neurological and psychiatric disorders. Here we have developed a homology model of alpha 7 nAChR based on two high resolution crystal structures with Brookhaven Protein Data Bank (PDB) codes 2QC1 and 2WN9 for threading on one monomer and then for building a pentamer, respectively. A number of small molecule binding sites are identified using Pocket Finder (J. An, M. Tortov, and R. Abagyan, Molecular & Cellular Proteomics, 4.6, 752-761 (2005)) of Internal Coordinate Mechanics (ICM). Remarkably, these computer-identified sites match perfectly with ordered solvent densities found in the high-resolution crystal structure of at nAChR, suggesting that the surface cavities in the alpha 7 nAChR model are likely binding sites of small molecules. A high throughput virtual screening by flexible ligand docking of 5008 small molecule compounds was performed at three potential allosteric modulator (AM) binding sites of alpha 7 nAChR using Molsoft ICM software (R. Abagyan, M. Tortov and D. Kuznetsov, J Comput Chem 15, 488-506, (1994)). Some experimentally verified allosteric modulators of alpha 7 like CCMI comp-6, LY 7082101, 5-HI, TQS, PNU-120596, genistein, and NS-1738 ranked among top 100 compounds, while the rest of the compounds in the list could guide further search for new allosteric modulators.
引用
收藏
页码:695 / 715
页数:21
相关论文
共 92 条
[71]   Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors [J].
Samochocki, M ;
Höffle, A ;
Fehrenbacher, A ;
Jostock, R ;
Ludwig, J ;
Christner, C ;
Radina, M ;
Zerlin, M ;
Ullmer, C ;
Pereira, EFR ;
Lübbert, H ;
Albuquerque, EX ;
Maelicke, A .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 305 (03) :1024-1036
[72]  
SEGUELA P, 1993, J NEUROSCI, V13, P596
[73]   Nicotinic acetylcholine receptors as targets for antidepressants [J].
Shytle, RD ;
Silver, AA ;
Lukas, RJ ;
Newman, MB ;
Sheehan, DV ;
Sanberg, PR .
MOLECULAR PSYCHIATRY, 2002, 7 (06) :525-535
[74]  
Sieghart W., 2002, Current Topics in Medicinal Chemistry, V2, P795, DOI 10.2174/1568026023393507
[75]   Computational Study of the Sulfonylated Amino Acid Hydroxamates Binding to the Zinc Ion within the Active Site of Carbonic Anhydrase [J].
Sille, Julius ;
Remko, Milan .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2009, 26 (04) :431-444
[76]   In Silico Structural and Functional Analysis of Fragments of the Ankyrin Repeat Protein P18INK4c [J].
Sklenovsky, Petr ;
Otyepka, Michal .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2010, 27 (04) :521-539
[77]   Molecular Modeling Studies of the Interaction Between Plasmodium falciparum HslU and HslV Subunits [J].
Subramaniam, Sangeetha ;
Mohmmed, Asif ;
Gupta, Dinesh .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2009, 26 (04) :473-479
[78]   Sequence Analysis, Structure Prediction, and Functional Validation of phaC1/phaC2 Genes of Pseudomonas sp LDC-25 and Its Importance in Polyhydroxyalkanoate Accumulation [J].
Sujatha, Kabilan ;
Mahalakshmi, Ayyasamy ;
Solaiman, Daniel K. Y. ;
Shenbagarathai, Rajaiah .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2009, 26 (06) :771-779
[79]   Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors [J].
Taly, Antoine ;
Corringer, Pierre-Jean ;
Grutter, Thomas ;
de Carvalho, Lia Prado ;
Karplus, Martin ;
Changeux, Jean-Pierre .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (45) :16965-16970
[80]   Discovery of the α7 nicotinic acetylcholine receptor agonists.: (R)-3′-(5-Chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5′-[1′,3′]-oxazolidin-2′-one as a novel, potent, selective, and orally bioavailable ligand [J].
Tatsumi, R ;
Fujio, M ;
Satoh, H ;
Katayama, J ;
Takanashi, S ;
Hashimoto, K ;
Tanaka, H .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (07) :2678-2686