Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Shen, Mingyun ^a,c   Tian, Sheng ^c   Pan, Peichen ^a   Sun, Huiyong ^a   Li, Dan ^a   Li, Youyong ^c   Zhou, Hefeng ^d   Li, Chuwen ^d   Lee, Simon Ming Yuen ^d   Hou, Tingjun ^a,b  

^a ZHEJIANG UNIVERSITY   (China)

^b ZHEJIANG UNIVERSITY   (China)

^c SOOCHOW UNIVERSITY   (China)

^d UNIVERSITY OF MACAU   (Macao)

Author keywords

[No Author keywords available]

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; ACTIN DEPOLYMERIZING FACTOR; AMIDE; ATORVASTATIN; PROTEIN KINASE INHIBITOR; PYRIDINE DERIVATIVE; PYRROLE DERIVATIVE; PYRROLO(2, 3-B)PYRIDINE; RHO KINASE; ROCK1 PROTEIN, HUMAN;

ANIMAL; ANTAGONISTS AND INHIBITORS; BINDING SITE; CEREBRAL HEMORRHAGE; CHEMICAL DATABASE; CHEMICALLY INDUCED; CHEMISTRY; DISEASE MODEL; DRUG EFFECTS; ENZYME ACTIVATION; HUMAN; IC50; METABOLISM; MOLECULAR DOCKING; PHOSPHORYLATION; PROTEIN DATABASE; PROTEIN TERTIARY STRUCTURE; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; UMBILICAL VEIN ENDOTHELIAL CELL; ZEBRA FISH;

ACTIN DEPOLYMERIZING FACTORS; AMIDES; ANIMALS; ATORVASTATIN CALCIUM; BINDING SITES; CEREBRAL HEMORRHAGE; DATABASES, CHEMICAL; DATABASES, PROTEIN; DISEASE MODELS, ANIMAL; ENZYME ACTIVATION; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR DOCKING SIMULATION; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PYRIDINES; PYRROLES; RHO-ASSOCIATED KINASES; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; ZEBRAFISH;

EID: 84947059490     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep16749     Document Type: Article

References (63)

1. Nakagawa, O. et al. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 392, 189-193 (1996).
2. Ishizaki, T. et al. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 15, 1885 (1996).
3. Matsui, T. et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 15, 2208 (1996).
4. Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241 (2000).
5. Pan, P. C. et al. Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. Drug Discov. Today 18, 1323-1333 (2013).
6. Peterson, R. T. & Schreiber, S. L. Kinase phosphorylation: Keeping it all in the family. Curr. Biol. 9, R521-R524 (1999).
7. Sebbagh, M. et al. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nature Cell Biol. 3, 346-352 (2001).
8. Leung, T., Chen, X. Q., Manser, E. & Lim, L. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol. Cell. Biol. 16, 5313 (1996).
9. Amano, M., Nakayama, M. & Kaibuchi, K. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton 67, 545-554 (2010).
10. Uehata, M. et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389, 990-993 (1997).
11. Itoh, K. et al. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nature Med. 5, 221-225 (1999).
12. Hara, M. et al. Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats. J. Neurosurg.-Spine 93, 94-101 (2000).
13. Kandabashi, T. et al. Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1. Circulation 101, 1319-1323 (2000).
14. Honjo, M. et al. Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes. Arch. Ophthalmol. 119, 1171 (2001).
15. Dergham, P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570-6577 (2002).
16. Kamai, T. et al. The rho/rho-kinase pathway is involved in the progression of testicular germ cell tumour. BJU Int. 89, 449-453 (2002).
17. Kamai, T. et al. Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin. Cancer Res. 9, 2632-2641 (2003).
18. Feng, Y. et al. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem. 51, 6642-6645 (2008).
19. Sessions, E. H. et al. Benzimidazole- and benzoxazole-based inhibitors of Rho kinase. Bioorg. Med. Chem. Lett. 18, 6390-6393 (2008).
20. Davis, R. L. et al. Benzothiophene containing Rho kinase inhibitors: Efficacy in an animal model of glaucoma. Bioorg. Med. Chem. Lett. 20, 3361-3366 (2010).
21. Shen, M. et al. Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations. Mol. Biosyst. 9, 361-374 (2013).
22. Mueller, B. K., Mack, H. & Teusch, N. Rho kinase, a promising drug target for neurological disorders. Nature Rev. Drug Discov. 4, 387-398 (2005).
23. Kikuchi, Y. et al. A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J. Endocrinol. 192, 595 (2007).
24. Mizuno, K. et al. Ocular hypotensive and neuroprotective effects of K-115, a novel Rho-kinase inhibitor. Invest. Ophth. Vis. Sci. 48, 4805 (2007).
25. Peterson, W. et al. Topical administration of a novel and potent Rho kinase (ROK) inhibitor INS117548 alters the actin cytoskeleton, effectively lowers IOP, and is well tolerated on the ocular surface. Invest. Ophth. Vis. Sci. 49, 3816 (2008).
26. Löhn, M. et al. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension 54, 676-683 (2009).
27. Williams, R. D., Novack, G. D., van Haarlem, T. & Kopczynski, C. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol. 152, 834-841 (2011).
28. Tokushige, H. et al. Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest. Ophth. Vis. Sci. 48, 3216-3222 (2007).
29. Koppen, H. Virtual screening - What does it give us? Curr. Opin. Drug Disc. Dev. 12, 397-407 (2009).
30. Tanrikulu, Y., Kruger, B. & Proschak, E. The holistic integration of virtual screening in drug discovery. Drug Discov. Today 18, 358-364 (2013).
31. Amaro, R. E. & Li, W. W. Emerging Methods for Ensemble-Based Virtual Screening. Curr. Top. Med. Chem. 10, 3-13 (2010).
32. Cosconati, S. et al. Protein flexibility in virtual screening: the BACE-1 case study. J. Chem. Inf. Model. 52, 2697-2704 (2012).
33. Totrov, M. & Abagyan, R. Flexible ligand docking to multiple receptor conformations: a practical alternative. Curr. Opin. Struc. Biol. 18, 178-184 (2008).
34. McCammon, J. A. Target flexibility in molecular recognition. BBA-Proteins Proteom. 1754, 221-224 (2005).
35. Carlson, H. A. Protein flexibility and drug design: how to hit a moving target. Curr. Opin. Chem. Biol. 6, 447-452 (2002).
36. Cheng, L. S. et al. Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase. J. Med. Chem. 51, 3878-3894 (2008).
37. Nichols, S. E., Swift, R. V. & Amaro, R. E. Rational prediction with molecular dynamics for hit identification. Curr. Top. Med. Chem. 12, 2002-2012 (2012).
38. Sinko, W., Lindert, S. & McCammon, J. A. Accounting for Receptor Flexibility and Enhanced Sampling Methods in Computer-Aided Drug Design. Chem. Biol. Drug Des. 81, 41-49 (2013).
39. Huang, S. & Zou, X. Ensemble docking of multiple protein structures: Considering protein structural variations in molecular docking. Proteins 66, 399-421 (2007).
40. Lexa, K. W. & Carlson, H. A. Protein flexibility in docking and surface mapping. Q. Rev. Biophysics 45, 301-343 (2012).
41. Tian, S. et al. Assessing an ensemble docking-based virtual screening strategy for kinase targets by considering protein flexibility. J. Chem. Inf. Model. 54, 2664-2679 (2014).
42. Tian, S. et al. Development and evaluation of an integrated virtual screening strategy by combining molecular docking and pharmacophore searching based on multiple protein structures. J. Chem. Inf. Model. 53, 2743-2756 (2013).
43. Shen, M. et al. Discovery of Rho-kinase inhibitors by docking-based virtual screening. Mol. Biosyst. 9, 1511-1521 (2013).
44. Jacobs, M. et al. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J. Biol. Chem. 281, 260-268 (2006).
45. Komander, D., Garg, R., Wan, P. T. C., Ridley, A. J. & Barford, D. Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure. EMBO J. 27, 3175-3185 (2008).
46. Bosanac, T. et al. Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 3, aryl substituted pyrrolidines. Bioorg. Med. Chem. Lett. 20, 3746-3749 (2010).
47. Li, R. et al. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J. Med. Chem. 55, 2474-2478 (2012).
48. Patel, R. A. et al. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-Invasive and antitumor activities in breast cancer. Cancer Res. 72, 5025-5034 (2012).
49. Gohlke, H., Kiel, C. & Case, D. A. Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. J. Mol. Biol. 330, 891-914 (2003).
50. Liu, T., Lin, Y., Wen, X., Jorissen, R. N. & Gilson, M. K. BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 35, D198-D201 (2007).
51. Hou, T., Li, N., Li, Y. & Wang, W. Characterization of domain-peptide interaction interface: prediction of SH3 domain-mediated protein-protein interaction network in yeast by generic structure-based models. J. Proteome Res. 11, 2982-2995 (2012).
52. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Ad. Drug Deliver. Rev. 23, 3-25 (1997).
53. Walters, W. P., Stahl, M. T. & Murcko, M. A. Virtual screening - an overview. Drug Discov. Today 3, 160-178 (1998).
54. Tian, S., Wang, J., Li, Y., Xu, X. & Hou, T. Drug-likeness analysis of Traditional Chinese Medicines: prediction of drug-likeness using machine learning approaches. Mol. Pharmaceut. 9, 2875-2886 (2012).
55. Gohlke, H. & Klebe, G. Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Angew. Chem. Int. Edit. 41, 2644-2676 (2002).
56. Gjini, E. et al. Zebrafish Tie-2 shares a redundant role with Tie-1 in heart development and regulates vessel integrity. Dis. Mod. Mech. 4, 57-66 (2011).
57. Sun, H. et al. Assessing the performance of MM/PBSA and MM/GBSA methods. 5. Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring. Phys. Chem. Chem. Phys. 16, 22035-22045 (2014).
58. Xu, L., Sun, H., Li, Y., Wang, J. & Hou, T. Assessing the performance of MM/PBSA and MM/GBSA methods. 3. the impact of force fields and ligand charge models. J. Phys. Chem. B 117, 8408-8421 (2013).
59. Hou, T. J., Wang, J. M., Li, Y. Y. & Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model. 51, 69-82 (2011).
60. Homeyer, N. & Gohlke, H. Free Energy Calculations by the Molecular Mechanics Poisson-Boltzmann Surface Area Method. Mol. Inf. 31, 114-122 (2012).
61. Kollman, P. A. et al. Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Accounts Chem Res 33, 889-897 (2000).
62. Li, S. et al. Basal Flt1 tyrosine kinase activity is a positive regulator of endothelial survival and vascularization during zebrafish embryogenesis. BBA-Gen. Subjects (2014).
63. DesMarais, V., Ghosh, M., Eddy, R. & Condeelis, J. Cofilin takes the lead. J. Cell Sci. 118, 19-26, doi: 10.1242/jcs.1631.01631 (2005).