Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics

Journal of Medicinal Chemistry

Volumn 59, Issue 4, 2016, Pages 1340-1349

  Xu, Min ^a   Unzue, Andrea ^a   Dong, Jing ^a   Spiliotopoulos, Dimitrios ^a   Nevado, Cristina ^a   Caflisch, Amedeo ^a  

^a UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

BROMODOMAIN INHIBITOR; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN BINDING PROTEIN; GUANIDINE; BENZENE DERIVATIVE; CREBBP PROTEIN, HUMAN; LIGAND; MOLECULAR LIBRARY; PROTEIN BINDING; PYRROLE DERIVATIVE;

ARTICLE; CONTROLLED STUDY; DISSOCIATION CONSTANT; DRUG BINDING SITE; DRUG CONFORMATION; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HYDROGEN BOND; IC50; MOLECULAR DOCKING; MOLECULAR DYNAMICS; PROTEIN SECONDARY STRUCTURE; PROTEIN STRUCTURE; RECEIVER OPERATING CHARACTERISTIC; ACYLATION; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DESIGN; DRUG EFFECTS; HUMAN; METABOLISM; MOLECULAR LIBRARY; PHARMACOLOGY; PROTEIN TERTIARY STRUCTURE;

ACYLATION; BENZENE DERIVATIVES; CREB-BINDING PROTEIN; DRUG DESIGN; HUMANS; LIGANDS; MOLECULAR DOCKING SIMULATION; MOLECULAR DYNAMICS SIMULATION; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PYRROLES; SMALL MOLECULE LIBRARIES;

EID: 84959420872     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00171     Document Type: Article

References (44)

1. Sanchez, R.; Meslamani, J.; Zhou, M. M. The bromodomain: from epigenome reader to druggable target Biochim. Biophys. Acta, Gene Regul. Mech. 2014, 1839, 676-685 10.1016/j.bbagrm.2014.03.011
2. Filippakopoulos, P.; Knapp, S. The bromodomain interaction module FEBS Lett. 2012, 586, 2692-2704 10.1016/j.febslet.2012.04.045
3. Filippakopoulos, P.; Picaud, S.; Mangos, M.; Keates, T.; Lambert, J. P.; Barsyte-Lovejoy, D.; Felletar, I.; Volkmer, R.; Muller, S.; Pawson, T.; Gingras, A. C.; Arrowsmith, C. H.; Knapp, S. Histone recognition and large-scale structural analysis of the human bromodomain family Cell 2012, 149, 214-231 10.1016/j.cell.2012.02.013
4. Sachchidanand; Resnick-Silverman, L.; Yan, S.; Mutjaba, S.; Liu, W.; Zeng, L.; Manfredi, J. J.; Zhou, M.-M. Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein Association Chem. Biol. 2006, 13, 81-90 10.1016/j.chembiol.2005.10.014
5. Borah, J. C.; Mujtaba, S.; Karakikes, I.; Zeng, L.; Muller, M.; Patel, J.; Moshkina, N.; Morohashi, K.; Zhang, W.; Gerona-Navarro, G.; Hajjar, R. J.; Zhou, M. M. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes Chem. Biol. 2011, 18, 531-541 10.1016/j.chembiol.2010.12.021
6. Gerona-Navarro, G.; Yoel, R.; Mujtaba, S.; Frasca, A.; Patel, J.; Zeng, L.; Plotnikov, A. N.; Osman, R.; Zhou, M. M. Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors J. Am. Chem. Soc. 2011, 133, 2040-2043 10.1021/ja107761h
7. Philpott, M.; Yang, J.; Tumber, T.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Keates, T.; Felletar, I.; Ciulli, A.; Knapp, S.; Heightman, T. D. Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery Mol. BioSyst. 2011, 7, 2899-2908 10.1039/c1mb05099k
8. Hewings, D. S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.; Heightman, T. D. 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands J. Med. Chem. 2011, 54, 6761-6770 10.1021/jm200640v
9. Chung, C.-w.; Dean, A. W.; Woolven, J. M.; Bamborough, P. Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery J. Med. Chem. 2012, 55, 576-586 10.1021/jm201320w
10. Hay, D.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Philpott, M.; Picaud, S.; Hewings, D. S.; Uttakar, S.; Heightman, T. D.; Conway, S. J.; Knapp, S.; Brennan, P. E. The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains MedChemComm 2013, 4, 140-144 10.1039/C2MD20189E
11. Hay, D. A.; Fedorov, O.; Martin, S.; Singleton, D. C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M. E.; Muller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E. Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains J. Am. Chem. Soc. 2014, 136, 9308-9319 10.1021/ja412434f
12. I-CBP112-a CREBBP/EP300-selective chemical probe. http://www.thesgc.org/chemical-probes/ICBP112.
13. Rooney, T. P.; Filippakopoulos, P.; Fedorov, O.; Picaud, S.; Cortopassi, W. A.; Hay, D. A.; Martin, S.; Tumber, A.; Rogers, C. M.; Philpott, M.; Wang, M.; Thompson, A. L.; Heightman, T. D.; Pryde, D. C.; Cook, A.; Paton, R. S.; Muller, S.; Knapp, S.; Brennan, P. E.; Conway, S. J. A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-pi interaction Angew. Chem., Int. Ed. 2014, 53, 6126-6130 10.1002/anie.201402750
14. Fedorov, O.; Lingard, H.; Wells, C.; Monteiro, O. P.; Picaud, S.; Keates, T.; Yapp, C.; Philpott, M.; Martin, S. J.; Felletar, I.; Marsden, B. D.; Filippakopoulos, P.; Muller, S.; Knapp, S.; Brennan, P. E. [1,2,4]triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains J. Med. Chem. 2014, 57, 462-476 10.1021/jm401568s
15. Kolb, P.; Kipouros, C. B.; Huang, D.; Caflisch, A. Structure-based tailoring of compound libraries for high-throughput screening: Discovery of novel EphB4 kinase inhibitors Proteins: Struct., Funct., Genet. 2008, 73, 11-18 10.1002/prot.22028
16. Zhao, H.; Dong, J.; Lafleur, K.; Nevado, C.; Caflisch, A. Discovery of a Novel Chemotype of Tyrosine Kinase Inhibitors by Fragment-Based Docking and Molecular Dynamics ACS Med. Chem. Lett. 2012, 3, 834-838 10.1021/ml3001984
17. Kolb, P.; Caflisch, A. Automatic and Efficient Decomposition of Two-Dimensional Structures of Small Molecules for Fragment-Based High-Throughput Docking J. Med. Chem. 2006, 49, 7384-7392 10.1021/jm060838i
18. Majeux, N.; Scarsi, M.; Apostolakis, J.; Ehrhardt, C.; Caflisch, A. Exhaustive Docking of Molecular Fragments With Electrostatic Solvation Proteins: Struct., Funct., Genet. 1999, 37, 88-105 10.1002/(SICI)1097-0134(19991001)37:1<88::AID-PROT9>3.3.CO;2-F
19. Majeux, N.; Scarsi, M.; Caflisch, A. Efficient electrostatic solvation model for protein-fragment docking Proteins: Struct., Funct., Genet. 2001, 42, 256-268 10.1002/1097-0134(20010201)42:2<256::AID-PROT130>3.0.CO;2-4
20. Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C. Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00172.
21. Steiner, S.; Magno, A.; Huang, D.; Caflisch, A. Does bromodomain flexibility influence histone recognition? FEBS Lett. 2013, 587, 2158-2163 10.1016/j.febslet.2013.05.032
22. Chung, C.-w.; Coste, H.; White, J. H.; Mirguet, O.; Wilde, J.; Gosmini, R. L.; Delves, C.; Magny, S. M.; Woodward, R.; Hughes, S. A.; Boursier, E. V.; Flynn, H.; Bouillot, A. M.; Bamborough, P.; Brusq, J.-M. G.; Gellibert, F. J.; Jones, E. J.; Riou, A. M.; Homes, P.; Martin, S. L.; Uings, I. J.; Toum, J.; Clément, C. A.; Boullay, A.-B.; Grimley, R. L.; Blandel, F. M.; Prinjha, R. K.; Lee, K.; Kirilovsky, J.; Nicodeme, E. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains J. Med. Chem. 2011, 54, 3827-3838 10.1021/jm200108t
23. Brooks, B. R.; Brooks, C. L., 3rd; Mackerell, A. D., Jr.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J. Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M. CHARMM: the biomolecular simulation program J. Comput. Chem. 2009, 30, 1545-1614 10.1002/jcc.21287
24. Zhao, H.; Huang, D. Hydrogen Bonding Penalty upon Ligand Binding PLoS One 2011, 6, e19923 10.1371/journal.pone.0019923
25. Filippakopoulos, P.; Knapp, S. Targeting bromodomains: epigenetic readers of lysine acetylation Nat. Rev. Drug Discovery 2014, 13, 337-356 10.1038/nrd4286
26. Trott, O.; Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading J. Comput. Chem. 2010, 31, 455-461 10.1002/jcc.21334
27. Fabian, M. A.; Biggs, W. H., 3rd; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lelias, J. M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors Nat. Biotechnol. 2005, 23, 329-336 10.1038/nbt1068
28. Quinn, E.; Wodicka, L.; Ciceri, P.; Pallares, G.; Pickle, E.; Torrey, A.; Hunt, J.; Treiber, D. BROMOscan-a high throughput, quantitative ligand binding platform identifies best-in-class bromodomain inhibitors from a screen of mature compounds targeting other protein classes Cancer Res. 2013, 73, 4238 10.1158/1538-7445.AM2013-4238
29. Magno, A.; Steiner, S.; Caflisch, A. Mechanism and Kinetics of Acetyl-Lysine Binding to Bromodomains J. Chem. Theory Comput. 2013, 9, 4225-4232 10.1021/ct400361k
30. Lucas, X.; Wohlwend, D.; Hügle, M.; Schmidtkunz, K.; Gerhardt, S.; Schüle, R.; Jung, M.; Einsle, O.; Günther, S. 4-Acyl Pyrroles: Mimicking Acetylated Lysines in Histone Code Reading Angew. Chem., Int. Ed. 2013, 52, 14055-14059 10.1002/anie.201307652
31. Ferguson, F. M.; Fedorov, O.; Chaikuad, A.; Philpott, M.; Muniz, J. R. C.; Felletar, I.; von Delft, F.; Heightman, T.; Knapp, S.; Abell, C.; Ciulli, A. Targeting low druggability bromodomains: Fragment based screening and inhibitor design against the BAZ2B bromodomain J. Med. Chem. 2013, 56, 10183-101837 10.1021/jm401582c
32. Blöchliger, N.; Vitalis, A.; Caflisch, A. A scalable algorithm to order and annotate continuous observations reveals the metastable states visited by dynamical systems Comput. Phys. Commun. 2013, 184, 2446-2453 10.1016/j.cpc.2013.06.009
33. Blöchliger, N.; Vitalis, A.; Caflisch, A. High-resolution visualisation of the States and pathways sampled in molecular dynamics simulations Sci. Rep. 2014, 4, 6264 10.1038/srep06264
34. Lafleur, K.; Huang, D.; Zhou, T.; Caflisch, A.; Nevado, C. Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4) J. Med. Chem. 2009, 52, 6433-6446 10.1021/jm9009444
35. Zhao, H.; Gartenmann, L.; Dong, J.; Spiliotopoulos, D.; Caflisch, A. Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking Bioorg. Med. Chem. Lett. 2014, 24, 2493-2496 10.1016/j.bmcl.2014.04.017
36. Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A. D. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields J. Comput. Chem. 2010, 31, 671-690 10.1002/jcc.21367
37. Yesselman, J. D.; Price, D. J.; Knight, J. L.; Brooks, C. L. MATCH: An atom-typing toolset for molecular mechanics force fields J. Comput. Chem. 2012, 33, 189-202 10.1002/jcc.21963
38. Huang, D.; Rossini, E.; Steiner, S.; Caflisch, A. Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent ChemMedChem 2014, 9, 573-579 10.1002/cmdc.201300156
39. Scarsi, M.; Apostolakis, J.; Caflisch, A. Continuum Electrostatic Energies of Macromolecules in Aqueous Solutions J. Phys. Chem. A 1997, 101, 8098-8106 10.1021/jp9714227
40. Scarsi, M.; Apostolakis, J.; Caflisch, A. Comparison of a GB Solvation Model with Explicit Solvent Simulations: Potentials of Mean Force and Conformational Preferences of Alanine Dipeptide and 1,2-Dichloroethane J. Phys. Chem. B 1998, 102, 3637-3641 10.1021/jp980506s
41. Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation J. Chem. Theory Comput. 2008, 4, 435-447 10.1021/ct700301q
42. Pronk, S.; Páll, S.; Schulz, R.; Larsson, P.; Bjelkmar, P.; Apostolov, R.; Shirts, M. R.; Smith, J. C.; Kasson, P. M.; van der Spoel, D.; Hess, B.; Lindahl, E. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit Bioinformatics 2013, 29, 845-854 10.1093/bioinformatics/btt055
43. Jorgensen, W. L.; Madura, J. D. Quantum and statistical mechanical studies of liquids. 25. Solvation and conformation of methanol in water J. Am. Chem. Soc. 1983, 105, 1407-1413 10.1021/ja00344a001
44. Vitalis, A.; Caflisch, A. Efficient Construction of Mesostate Networks from Molecular Dynamics Trajectories J. Chem. Theory Comput. 2012, 8, 1108-1120 10.1021/ct200801b