Fragment-Based Approach to Targeting Inosine-5′-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis

Journal of Medicinal Chemistry

Volumn 61, Issue 7, 2018, Pages 2806-2822

  Trapero, Ana ^a   Pacitto, Angela ^a   Singh, Vinayak ^b,d   Sabbah, Mohamad ^a   Coyne, Anthony G ^a   Mizrahi, Valerie ^b   Blundell, Tom L ^a   Ascher, David B ^a,c   Abell, Chris ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF CAPE TOWN   (South Africa)

^c UNIVERSITY OF MELBOURNE   (Australia)

^d UNIVERSITY OF CAPE TOWN   (South Africa)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 (1H IMIDAZOL 4 YL)PHENYL] 3 [[5 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]METHYL)UREA; 2 CHLORO N (4 IODOPHENYL)ACETAMIDE; 2 CHLORO N PHENYLACETAMIDE; 2 [(4 PHENYL 1H IMIDAZOL 2 YL)THIO]ACETIC ACID; 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY] N (4 PHENYL 1H IMIDAZOL 2 YL)PROPANAMIDE; 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY] N PHENYLPROPANAMIDE; 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY] N [4 (4 MORPHOLINOPHENYL) 1H IMIDAZOL 2 YL]PROPANAMIDE; 2 [[4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]THIO] N (4 IODOPHENYL)ACETAMIDE; 2 [[4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]THIO] N PHENYLACETAMIDE; 2 [[4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]THIO]ACETIC ACID; INOSINATE DEHYDROGENASE; INOSINATE DEHYDROGENASE INHIBITOR; N (4 IODOPHENYL) 2 [(4 PHENYL 1H IMIDAZOL 2 YL)THIO]ACETAMIDE; N (4 IODOPHENYL) 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY]PROPANAMIDE; N (BENZOFURAN 5 YL) 2 CHLOROACETAMIDE; N (BENZOFURAN 5 YL) 2 [(4 PHENYL 1H IMIDAZOL 2 YL)THIO]ACETAMIDE; N (BENZOFURAN 5 YL) 2 [[4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]THIO]ACETAMIDE; N ISOPROPYL 2 [(4 PHENYL 1H IMIDAZOL 2 YL)THIO]ACETAMIDE; N PHENYL 2 [(4 PHENYL 1H IMIDAZOL 2 YL)THIO]ACETAMIDE; N [4 (1H IMIDAZOL 4 YL)PHENYL] 2 CHLOROACETAMIDE; N [4 (1H IMIDAZOL 4 YL)PHENYL] 2 [(4 PHENYL 1H IMIDAZOL 2 YL)THIO]ACETAMIDE; N [4 (1H IMIDAZOL 4 YL)PHENYL] 2 [[4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]THIO]ACETAMIDE; N [4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL] 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY]PROPANAMIDE; N [4 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]ACETAMIDE; N [4 (4 BROMOPHENYL)OXAZOL 2 YL] 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY]PROPANAMIDE; N [4 (4 IODOPHENYL) 1H IMIDAZOL 2 YL] 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY]PROPANAMIDE; N [4 (4 METHOXYPHENYL) 1H IMIDAZOL 2 YL] 2 [4 (1 METHYL 1H IMIDAZOL 4 YL)PHENOXY]PROPANAMIDE; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; [5 (4 BROMOPHENYL) 1H IMIDAZOL 2 YL]METHANAMINE HYDROCHLORIDE; ENZYME INHIBITOR; NICOTINAMIDE ADENINE DINUCLEOTIDE; PEPTIDE FRAGMENT;

ARTICLE; BACTERIAL GROWTH; COMPARATIVE STUDY; CROSS LINKING; CRYSTALLIZATION; DRUG SCREENING; DRUG SYNTHESIS; ENANTIOMER; HIGH THROUGHPUT SCREENING; HYDROGEN BOND; IC50; IN VITRO STUDY; INHIBITION CONSTANT; LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY; MEMBRANE PERMEABILITY; METABOLIC STABILITY; MORTALITY; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PROTEIN PURIFICATION; TUBERCULOSIS; X RAY CRYSTALLOGRAPHY; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECT; ENZYMOLOGY; METABOLISM; MICROBIAL SENSITIVITY TEST; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANTITUBERCULAR AGENTS; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HIGH-THROUGHPUT SCREENING ASSAYS; IMP DEHYDROGENASE; MICROBIAL SENSITIVITY TESTS; MYCOBACTERIUM TUBERCULOSIS; NAD; PEPTIDE FRAGMENTS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85045584564     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.7b01622     Document Type: Article

References (50)

1. WHO. Tuberculosis: Fact sheet; World Health Organization 2016: Geneva, Switzerland. 2016.
2. Onyebujoh, P.; Zumla, A.; Ribeiro, I.; Rustomjee, R.; Mwaba, P.; Gomes, M.; Grange, J. M. Treatment of tuberculosis: present status and future prospects. Bull. World Health Organ. 2005, 83, 857-865
3. Orenstein, E. W.; Basu, S.; Shah, N. S.; Andrews, J. R.; Friedland, G. H.; Moll, A. P.; Gandhi, N. R.; Galvani, A. P. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect. Dis. 2009, 9, 153-161, 10.1016/S1473-3099(09)70041-6
4. Ratcliffe, A. J. Inosine 5′-monophosphate dehydrogenase inhibitors for the treatment of autoimmune diseases. Curr. Opin. Drug Discovery Dev. 2006, 9, 595-605
5. Chen, L.; Pankiewicz, K. W. Recent development of IMP dehydrogenase inhibitors for the treatment of cancer. Curr. Opin. Drug Discovery Dev. 2007, 10, 403-412
6. Olah, E.; Kokeny, S.; Papp, J.; Bozsik, A.; Keszei, M. Modulation of cancer pathways by inhibitors of guanylate metabolism. Adv. Enzyme Regul. 2006, 46, 176-190, 10.1016/j.advenzreg.2006.01.002
7. Nair, V.; Shu, Q. Inosine monophosphate dehydrogenase as a probe in antiviral drug discovery. Antiviral Chem. Chemother. 2007, 18, 245-258, 10.1177/095632020701800501
8. Shu, Q.; Nair, V. Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery. Med. Res. Rev. 2008, 28, 219-232, 10.1002/med.20104
9. Shah, C. P.; Kharkar, P. S. Inosine 5′-monophosphate dehydrogenase inhibitors as antimicrobial agents: recent progress and future perspectives. Future Med. Chem. 2015, 7, 1415-1429, 10.4155/fmc.15.72
10. Hedstrom, L.; Liechti, G.; Goldberg, J. B.; Gollapalli, D. R. The antibiotic potential of prokaryotic IMP dehydrogenase inhibitors. Curr. Med. Chem. 2011, 18, 1909-1918, 10.2174/092986711795590129
11. Hedstrom, L. IMP dehydrogenase: structure, mechanism, and inhibition. Chem. Rev. 2009, 109, 2903-2928, 10.1021/cr900021w
12. Jackson, R. C.; Weber, G.; Morris, H. P. IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature 1975, 256, 331-333, 10.1038/256331a0
13. Gilbert, H. J.; Lowe, C. R.; Drabble, W. T. Inosine 5′-monophosphate dehydrogenase of Escherichia coli. Purification by affinity chromatography, subunit structure and inhibition by guanosine 5′-monophosphate. Biochem. J. 1979, 183, 481-494, 10.1042/bj1830481
14. Lee, S. A.; Gallagher, L. A.; Thongdee, M.; Staudinger, B. J.; Lippman, S.; Singh, P. K.; Manoil, C. General and condition-specific essential functions of Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 5189-5194, 10.1073/pnas.1422186112
15. Valentino, M. D.; Foulston, L.; Sadaka, A.; Kos, V. N.; Villet, R. A.; Santa Maria, J., Jr.; Lazinski, D. W.; Camilli, A.; Walker, S.; Hooper, D. C.; Gilmore, M. S. Genes contributing to Staphylococcus aureus fitness in abscess- and infection-related ecologies. mBio 2014, 5, e01729-14, 10.1128/mBio.01729-14
16. Sassetti, C. M.; Boyd, D. H.; Rubin, E. J. Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 2003, 48, 77-84, 10.1046/j.1365-2958.2003.03425.x
17. Hedstrom, L. The bare essentials of antibiotic target validation. ACS Infect. Dis. 2017, 3, 2-4, 10.1021/acsinfecdis.6b00185
18. Petrelli, R.; Vita, P.; Torquati, I.; Felczak, K.; Wilson, D. J.; Franchetti, P.; Cappellacci, L. Novel inhibitors of inosine monophosphate dehydrogenase in patent literature of the last decade. Recent Pat. Anti-Cancer Drug Discovery 2013, 8, 103-125, 10.2174/1574892811308020001
19. Makowska-Grzyska, M.; Kim, Y.; Wu, R.; Wilton, R.; Gollapalli, D. R.; Wang, X. K.; Zhang, R.; Jedrzejczak, R.; Mack, J. C.; Maltseva, N.; Mulligan, R.; Binkowski, T. A.; Gornicki, P.; Kuhn, M. L.; Anderson, W. F.; Hedstrom, L.; Joachimiak, A. Bacillus anthracis inosine 5′-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-, substrate-, and product-bound complexes. Biochemistry 2012, 51, 6148-6163, 10.1021/bi300511w
20. Usha, V.; Gurcha, S. S.; Lovering, A. L.; Lloyd, A. J.; Papaemmanouil, A.; Reynolds, R. C.; Besra, G. S. Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against. Microbiology 2011, 157, 290-299, 10.1099/mic.0.042549-0
21. Makowska-Grzyska, M.; Kim, Y.; Gorla, S. K.; Wei, Y.; Mandapati, K.; Zhang, M.; Maltseva, N.; Modi, G.; Boshoff, H. I.; Gu, M.; Aldrich, C.; Cuny, G. D.; Hedstrom, L.; Joachimiak, A. Mycobacterium tuberculosis IMPDH in complexes with substrates, products and antitubercular compounds. PLoS One 2015, 10, e0138976 10.1371/journal.pone.0138976
22. Chen, L.; Wilson, D. J.; Xu, Y.; Aldrich, C. C.; Felczak, K.; Sham, Y. Y.; Pankiewicz, K. W. Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and. J. Med. Chem. 2010, 53, 4768-4778, 10.1021/jm100424m
23. Usha, V.; Hobrath, J. V.; Gurcha, S. S.; Reynolds, R. C.; Besra, G. S. Identification of novel Mt-Guab2 inhibitor series active against M. tuberculosis. PLoS One 2012, 7, e33886 10.1371/journal.pone.0033886
24. Park, Y.; Pacitto, A.; Bayliss, T.; Cleghorn, L. A.; Wang, Z.; Hartman, T.; Arora, K.; Ioerger, T. R.; Sacchettini, J.; Rizzi, M.; Donini, S.; Blundell, T. L.; Ascher, D. B.; Rhee, K. Y.; Breda, A.; Zhou, N.; Dartois, V.; Jonnala, S. R.; Via, L. E.; Mizrahi, V.; Epemolu, O.; Stojanovski, L.; Simeons, F. R.; Osuna-Cabello, M.; Ellis, L.; MacKenzie, C. J.; Smith, A. R.; Davis, S. H.; Murugesan, D.; Buchanan, K. I.; Turner, P. A.; Huggett, M.; Zuccotto, F.; Rebollo-Lopez, M. J.; Lafuente-Monasterio, M. J.; Sanz, O.; Santos Diaz, G.; Lelievre, J.; Ballell, L.; Selenski, C.; Axtman, M.; Ghidelli-Disse, S.; Pflaumer, H.; Boesche, M.; Drewes, G.; Freiberg, G.; Kurnick, M. D.; Srikumaran, M.; Kempf, D. J.; Green, S. R.; Ray, P. C.; Read, K. D.; Wyatt, P. G.; Barry Rd, C. E.; Boshoff, H. I. Essential but not vulnerable: indazole sulfonamides targeting inosine monophosphate dehydrogenase as potential leads against. ACS Infect. Dis. 2017, 3, 18-23, 10.1021/acsinfecdis.6b00103
25. Singh, V.; Donini, S.; Pacitto, A.; Sala, C.; Hartkoorn, R. C.; Dhar, N.; Keri, G.; Ascher, D. B.; Mondesert, G.; Vocat, A.; Lupien, A.; Sommer, R.; Vermet, H.; Lagrange, S.; Buechler, J.; Warner, D. F.; McKinney, J. D.; Pato, J.; Cole, S. T.; Blundell, T. L.; Rizzi, M.; Mizrahi, V. The inosine monophosphate dehydrogenase, GuaB2, is a vulnerable new bactericidal drug target for tuberculosis. ACS Infect. Dis. 2017, 3, 5-17, 10.1021/acsinfecdis.6b00102
26. Cox, J. A.; Mugumbate, G.; Del Peral, L. V.; Jankute, M.; Abrahams, K. A.; Jervis, P.; Jackenkroll, S.; Perez, A.; Alemparte, C.; Esquivias, J.; Lelievre, J.; Ramon, F.; Barros, D.; Ballell, L.; Besra, G. S. Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen. Sci. Rep. 2016, 6, 38986, 10.1038/srep38986
27. Moffat, J. G.; Vincent, F.; Lee, J. A.; Eder, J.; Prunotto, M. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat. Rev. Drug Discovery 2017, 16, 531-543, 10.1038/nrd.2017.111
28. Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. The challenge of new drug discovery for tuberculosis. Nature 2011, 469, 483-490, 10.1038/nature09657
29. Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discovery 2007, 6, 29-40, 10.1038/nrd2201
30. Scott, D. E.; Coyne, A. G.; Hudson, S. A.; Abell, C. Fragment-based approaches in drug discovery and chemical biology. Biochemistry 2012, 51, 4990-5003, 10.1021/bi3005126
31. Mendes, V.; Blundell, T. L. Targeting tuberculosis using structure-guided fragment-based drug design. Drug Discovery Today 2017, 22, 546-554, 10.1016/j.drudis.2016.10.003
32. Marchetti, C.; Chan, D. S.; Coyne, A. G.; Abell, C. Fragment-based approaches to TB drugs. Parasitology 2018, 145, 184-195, 10.1017/S0031182016001876
33. Wei, Y.; Kuzmic, P.; Yu, R.; Modi, G.; Hedstrom, L. Inhibition of inosine-5′-monophosphate dehydrogenase from Bacillus anthracis: Mechanism revealed by pre-steady-state kinetics. Biochemistry 2016, 55, 5279-5288, 10.1021/acs.biochem.6b00265
34. Dunkern, T.; Prabhu, A.; Kharkar, P. S.; Goebel, H.; Rolser, E.; Burckhard-Boer, W.; Arumugam, P.; Makhija, M. T. Virtual and experimental high-throughput screening (HTS) in search of novel inosine 5′-monophosphate dehydrogenase II (IMPDH II) inhibitors. J. Comput.-Aided Mol. Des. 2012, 26, 1277-1292, 10.1007/s10822-012-9615-5
35. Gorla, S. K.; Kavitha, M.; Zhang, M.; Chin, J. E.; Liu, X.; Striepen, B.; Makowska-Grzyska, M.; Kim, Y.; Joachimiak, A.; Hedstrom, L.; Cuny, G. D. Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase. J. Med. Chem. 2013, 56, 4028-4043, 10.1021/jm400241j
36. Kitagawa, H.; Ozawa, T.; Takahata, S.; Iida, M.; Saito, J.; Yamada, M. Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK. J. Med. Chem. 2007, 50, 4710-4720, 10.1021/jm0705354
37. Soh, C. H.; Chui, W. K.; Lam, Y. An efficient and expeditious synthesis of di- and monosubstituted 2-aminoimidazoles. J. Comb. Chem. 2008, 10, 118-122, 10.1021/cc700143n
38. Kumar, S.; Jaller, D.; Patel, B.; LaLonde, J. M.; DuHadaway, J. B.; Malachowski, W. P.; Prendergast, G. C.; Muller, A. J. Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase. J. Med. Chem. 2008, 51, 4968-4977, 10.1021/jm800512z
39. Jost, C.; Nitsche, C.; Scholz, T.; Roux, L.; Klein, C. D. Promiscuity and selectivity in covalent enzyme inhibition: a systematic study of electrophilic fragments. J. Med. Chem. 2014, 57, 7590-7599, 10.1021/jm5006918
40. Fortin, S.; Moreau, E.; Lacroix, J.; Cote, M. F.; Petitclerc, E.; Gaudreault, R. C. Synthesis, antiproliferative activity evaluation and structure-activity relationships of novel aromatic urea and amide analogues of N-phenyl-N'-(2-chloroethyl)ureas. Eur. J. Med. Chem. 2010, 45, 2928-2937, 10.1016/j.ejmech.2010.03.018
41. Bellina, F.; Guazzelli, N.; Lessi, M.; Manzini, C. Imidazole analogues of resveratrol: synthesis and cancer cell growth evaluation. Tetrahedron 2015, 71, 2298-2305, 10.1016/j.tet.2015.02.024
42. Ascher, D. B.; Cromer, B. A.; Morton, C. J.; Volitakis, I.; Cherny, R. A.; Albiston, A. L.; Chai, S. Y.; Parker, M. W. Regulation of insulin-regulated membrane aminopeptidase activity by its C-terminal domain. Biochemistry 2011, 50, 2611-2622, 10.1021/bi101893w
43. Kabsch, W. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 125-132, 10.1107/S0907444909047337
44. Adams, P. D.; Afonine, P. V.; Bunkoczi, G.; Chen, V. B.; Davis, I. W.; Echols, N.; Headd, J. J.; Hung, L. W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 213-221, 10.1107/S0907444909052925
45. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2126-2132, 10.1107/S0907444904019158
46. Jubb, H. C.; Higueruelo, A. P.; Ochoa-Montano, B.; Pitt, W. R.; Ascher, D. B.; Blundell, T. L. Arpeggio: A web server for calculating and visualising interatomic interactions in protein structures. J. Mol. Biol. 2017, 429, 365-371, 10.1016/j.jmb.2016.12.004
47. Pires, D. E.; Blundell, T. L.; Ascher, D. B. mCSM-lig: quantifying the effects of mutations on protein-small molecule affinity in genetic disease and emergence of drug resistance. Sci. Rep. 2016, 6, 29575, 10.1038/srep29575
48. Pires, D. E.; Ascher, D. B. CSM-lig: a web server for assessing and comparing protein-small molecule affinities. Nucleic Acids Res. 2016, 44, W557-61, 10.1093/nar/gkw390
49. Pires, D. E.; Blundell, T. L.; Ascher, D. B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015, 58, 4066-4072, 10.1021/acs.jmedchem.5b00104
50. Singh, V.; Brecik, M.; Mukherjee, R.; Evans, J. C.; Svetlikova, Z.; Blasko, J.; Surade, S.; Blackburn, J.; Warner, D. F.; Mikusova, K.; Mizrahi, V. The complex mechanism of antimycobacterial action of 5-fluorouracil. Chem. Biol. 2015, 22, 63-75, 10.1016/j.chembiol.2014.11.006