Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

详细信息    查看全文

• 作者：Zhiwei Feng ; Guanxing Hu ; Shifan Ma ; Xiang-Qun Xie
• 关键词：allosteric modulators ; bitopic ligands ; computational approaches ; drug discovery ; drug target discovery ; G protein ; coupled receptors
• 刊名：The AAPS Journal
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：17
• 期：5
• 页码：1080-1095
• 全文大小：3,774 KB
• 参考文献：1.Kenakin T, Miller LJ. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev. 2010;62:265-04.PubMed Central View Article PubMed
  2.Feng Z, Hou T, Li Y. Studies on the interactions between β2 adrenergic receptor and Gs protein by molecular dynamics simulations. J Chem Inf Model. 2012;52:1005-4.View Article PubMed
  3.Feng Z, Hou T, Li Y. Selectivity and activation of dopamine D3R from molecular dynamics. J Mol Model. 2012;18:5051-3.View Article PubMed
  4.Feng Z, Hou T, Li Y. Docking and MD study of histamine H4R based on the crystal structure of H1R. J Mol Graph Model. 2013;39:1-2.View Article PubMed
  5.Feng Z, Alqarni MH, Yang P, Tong Q, Chowdhury A, Wang L, et al. Modeling, molecular dynamics simulation and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J Chem Inf Model. 2014;54:2483-9.View Article PubMed
  6.Bridges TM, Lindsley CW. G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem Biol. 2008;3:530-1.View Article PubMed
  7.Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW. Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol. 2014;54:165-4.PubMed Central View Article PubMed
  8.Wellendorph P, Br?uner‐Osborne H. Molecular basis for amino acid sensing by family CG‐protein‐coupled receptors. Brit J Pharmacol. 2009;156:869-4.View Article
  9.Flor PJ, Acher FC. Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem Pharmacol. 2012;84:414-4.View Article PubMed
  10.Fenton AW. Allostery: an illustrated definition for the ‘second secret of life- Trends Biochem Sci. 2008;33:420-.PubMed Central View Article PubMed
  11.Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009;8:41-4.PubMed Central View Article PubMed
  12.Christopoulos A, Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol Rev. 2002;54:323-4.View Article PubMed
  13.Lane JR, Abdul-Ridha A, Canals M. Regulation of G protein-coupled receptors by allosteric ligands. ACS Chem Neurosci. 2013;4:527-4.PubMed Central View Article PubMed
  14.Melancon BJ, Hopkins CR, Wood MR, Emmitte KA, Niswender CM, Christopoulos A, et al. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem. 2012;55:1445-4.PubMed Central View Article PubMed
  15.Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, et al. ASD v2.0: updated content and novel features focusing on allosteric regulation. Nucleic Acids Res. 2014;42:D510-.PubMed Central View Article PubMed
  16.M?hler H, Fritschy J, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2-.View Article PubMed
  17.Epping-Jordan M, Le Poul E, Rocher J-P. Allosteric modulation: a novel approach to drug discovery. Innovations Pharm Technol. 2007;24:24-.
  18.Burford NT, Watson J, Bertekap R, Alt A. Strategies for the identification of allosteric modulators of G-protein-coupled receptors. Biochem Pharmacol. 2011;81:691-02.View Article PubMed
  19.Dalton J, Gómez-Santacana X, Llebaria A, Giraldo J. A computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (In) activation. J Chem Inf Model. 2014;54:1476-7.View Article PubMed
  20.Kamal M, Jockers R. Bitopic ligands: all-in-one orthosteric and allosteric. F1000 Biol Rep. 2009;1:77.PubMed Central PubMed
  21.Davie BJ, Christopoulos A, Scammells PJ. Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. ACS Chem Neurosci. 2013;4:1026-8.PubMed Central View Article PubMed
  22.Valant C, Sexton PM, Christopoulos A. Orthosteric/allosteric bitopic ligands. Mol Interv. 2009;9:125.View Article PubMed
  23.Valant C, Robert Lane J, Sexton PM, Christopoulos A. The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol. 2012;52:153-8.View Article PubMed
  24.Jo E, Bhhatarai B, Repetto E, Guerrero M, Riley S, Brown SJ, et al. Novel selective allosteric and bitopic ligands for the S1P3 receptor. ACS Chem Biol. 2012;7:1975-3.PubMed Central View Article PubMed
  25.Lane JR, Sexton PM, Christopoulos A. Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol Sci. 2013;34:59-6.View Article PubMed
  26.Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, et al. A new mechanism of allostery in a G protein–coupled receptor dimer. Nat Chem Biol. 2014;10:745-2.PubMed Central View Article PubMed
  27.Maggio R., Scarselli M., Capannolo M., Millan M. J. Novel dimensions of D3 receptor function: focus on
• 作者单位：Zhiwei Feng (1) (2) (3)
  Guanxing Hu (1) (2) (3)
  Shifan Ma (1) (2) (3)
  Xiang-Qun Xie (1) (2) (3) (4)
  
  1. Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, 3501 Terrace Street, 529 Salk Hall, Pittsburgh, Pennsylvania, 15261, USA
  2. NIDA National Center of Excellence for Computational Drug Abuse Research, Pittsburgh, Pennsylvania, USA
  3. Drug Discovery Institute, Pittsburgh, Pennsylvania, USA
  4. Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Biotechnology; Pharmacy;
• 出版者：Springer US
• ISSN：1550-7416

文摘

Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands. Radioligand binding and functional assays ([35S]GTPγS and ERK1/2 phosphorylation) are used to test the effects for potential modulators or bitopic ligands. High-throughput screening (HTS) in combination with disulfide trapping and fragment-based screening are used to aid the discovery of the allosteric modulators or bitopic ligands of GPCRs. When used alone, these methods are costly and can often result in too many potential drug targets, including false positives. Alternatively, low-cost and efficient computational approaches are useful in drug discovery of novel allosteric modulators and bitopic ligands to help refine the number of targets and reduce the false-positive rates. This review summarizes the state-of-the-art computational methods for the discovery of modulators and bitopic ligands. The challenges and opportunities for future drug discovery are also discussed.