Binding modes of diketo-acid inhibitors of HIV-1 integrase: A comparative molecular dynamics simulation study

Journal of Molecular Graphics and Modelling

Volumn 29, Issue 7, 2011, Pages 956-964

  Huang, Meilan ^a   Grant, Guy H ^b   Richards, W Graham ^c  

^a QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^c UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Catalytic loop; Diketo acid inhibitors; HIV 1 integrase; Ion pair interaction; Molecular dynamics

Indexed keywords

ACTION MECHANISMS; ACTIVE SITE; ATOMIC LEVELS; BINDING MODES; CATALYTIC LOOP; CATALYTIC SITES; DIKETO ACID INHIBITORS; DIKETO ACIDS; DRUG RESISTANCE; HIV-1 INTEGRASE; HIV-1 REVERSE TRANSCRIPTASE; INHIBITION MECHANISMS; ION-PAIR INTERACTIONS; MOLECULAR DYNAMICS SIMULATIONS; SALT BRIDGES; SELECTIVE INHIBITORS; STRUCTURAL INFORMATION;

BINDING ENERGY; DYNAMICS; IONS;

MOLECULAR DYNAMICS;

1 [5 (4 FLUOROBENZYL) 2 FURYL] 3 (1,2,4 TRIAZOL 3 YL) 1,3 PROPANEDIONE; 4 [1 (4 FLUOROBENZYL) 2 PYRROLYL] 2,4 DIOXOBUTYRIC ACID; ANTIVIRUS AGENT; DIKETO ACID INHIBITOR; ELVITEGRAVIR; INTEGRASE; L 708906; L 731927; L 731942; PROTEINASE; RALTEGRAVIR; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING SITE; CATALYSIS; DRUG BINDING SITE; DRUG POTENCY; HUMAN IMMUNODEFICIENCY VIRUS 1; MOLECULAR DYNAMICS; NONHUMAN; PRIORITY JOURNAL; SIMULATION;

HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HUMANS; MODELS, MOLECULAR; MOLECULAR DYNAMICS SIMULATION; MOLECULAR STRUCTURE; PROTEIN BINDING; PROTEIN CONFORMATION;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 79955870873     PISSN: 10933263     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jmgm.2011.04.002     Document Type: Article

References (53)

1. R. Dayam, N. Neamati, Small-molecule HIV-1 integrase inhibitors: the 2001-2002 update, Curr. Pharm. Des. 9 (2003) 1789-1802. (Pubitemid 36958350)
2. C. Maurin, F. Bailly, P. Cotelle, Structure - activity relationships of HIV-1 integrase inhibitors - enzyme - ligand interactions, Curr. Med. Chem. 10 (2003) 1795-1810. (Pubitemid 37038601)
3. A.L. Parrill, HIV-1 integrase Inhibition: binding sites structure - activity relationships and future perspectives, Curr. Med. Chem. 10 (2003) 1811-1824. (Pubitemid 37038602)
4. V. Nair, Novel inhibitors of HIV integrase: the discovery of potential anti-HIV therapeutic agents, Curr. Pharm. Des. 9 (2003) 2553-2565. (Pubitemid 37456009)
5. Y. Pommier, A.A. Johnson, C. Marchand, Integrase inhibitors to treat HIV/AIDS, Nat. Rev. Drug Discov. 4 (2005) 236-248. (Pubitemid 40372557)
6. A. Engelman, K. Mizuuchi, R. Craigie, HIV-1 DNA interaction - mechanism of viral-DNA cleavage and DNA strand transfer, Cell 67 (1991) 1211-1221. (Pubitemid 121001533)
7. J.C.H. Chen, J. Krucinski, L.J. Miercke, J.S. Finer-More, A.H. Tang, A.D. Leavitt, R.M. Stroud, Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: amodel for viral DNA binding, Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 8233-8238. (Pubitemid 30639655)
8. A. Engelman, F.D. Bushman, R. Craigie, Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex, EMBO (Eur. Mol. Biol. Organ) J. 12 (1993) 3269-3275. (Pubitemid 23232758)
9. D.C. Vangent, C. Vink, A.A.M.O. Groeneger, R.H.A. Plasterk, Complementation between HIV integrase proteins mutated in different domains, EMBO (Eur. Mol. Biol. Organ) J. 12 (1993) 3261-3267. (Pubitemid 23232757)
10. G. Buiacz, M. Jaskólski, J. Alexandratos, A. Wlodrawer, G. Merkek, R.A. Katz, A.M. Skalka, High-resolution structure of the catalytic domain of avain sarcoma virus integrase, J. Mol. Biol. 253 (1995) 333-346.
11. P.A. Rice, T.A. Baker, Comparative architecture of transposase and integrase complexes, Nat. Struct. Biol. 8 (2001) 302-307.
12. J.A. Grobler, K. Stillmock, B.H. Hu, M. Witmer, P. Felock, A.S. Espeseth, A. Wolfe, M. Egbertson, M. Bourgeois, J. Melamed, J.S. Wai, S. Young, J. Vacca, D.J. Hazuda, Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes, Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 6661-6666. (Pubitemid 34526189)
13. C. Marchand, A.A. Johnson, R.G. Karki, G.C.G. Pais, X.C. Zhang, K. Cowansage, T.A. Patel, M.C. Nicklaus, T.R. Burke, Y. Pommier, Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S), Mol. Pharmacol. 64 (2003) 600-609. (Pubitemid 37048563)
14. J. Greenwald, V. Le, S.L. Butler, F.D. Bushman, S. Choe, The mobility of an HIV-1 integrase active site loop is correlated with catalytic activity, Biochemistry 38 (1999) 8892-8898.
15. T.M. Jenkins, D. Esposito, A. Engelman, R. Craigie, Critical contacts between HIV-1 integrase and viral DNA identified by structure-based analysis and photo-crosslinking, EMBO (Eur. Mol. Biol. Organ) J. 16 (1997) 6849-6859. (Pubitemid 27503496)
16. D. Esposito, R. Craigie, Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein - DNA interaction, EMBO (Eur. Mol. Biol. Organ) J. 17 (1998) 5832-5843. (Pubitemid 28445994)
17. D.J. Hazuda, P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J.A. Grobler, A. Espeseth, L. Gabryelski, W. Schleif, C. Blau, M.D. Miller, Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells, Science 287 (2000) 646-650. (Pubitemid 30070911)
18. A. Billich, S-1360 Shionogi-GlaxoSmithKline, Curr. Opin. Investig. Drugs 4 (2003) 206-209.
19. D.J. Hazuda, N.J. Anthony, R.P. Gomez, S.M. Jolly, J.S. Wai, L. Zhuang, T.E. Fisher, M. Embrey, J.P. Guare, M.S. Egbertson, J.P. Vacca, J.R. Huff, P.J. Felock, M.V. Witmer, K.A. Stillmock, R. Danovich, J. Grobler, M.D. Miller, A.S. Espeseth, L. Jin, I.W. Chen, J.H. Lin, K. Kassahun, J.D. Ellis, B.K. Wong, W. Xu, P.G. Pearson, W.A. Schleif, R. Cortese, E. Emini, V. Summa, M.K. Holloway, S.D. Young, A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 11233-11238. (Pubitemid 39038330)
20. V. Fikkert, A. Hombrouck, B. Van Remoortel, M. De Maeyer, C. Pannecouque, E. De Clercq, Z. Debyser, M. Witvrouw, Multiple mutations in human immunodeficiency virus-1 integrase confer resistance to the clinical trial drug S-1360, AIDS 18 (2004) 2019-2028. (Pubitemid 39463355)
21. A. Zolopa, M. Mullen, D. Berger, P. Ruane, T. Hawkins, L. Zhong, S. Chuck, J. Enejosa, B. Kearney, A. Cheng, The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients, in: 14th Conf. RetroVir. Opportun. Infect, 2007, Abstract, 143LB.
22. T.H. Evering, M. Markowitz, Raltegravir: an integrase inhibitor for HIV-1, Expert Opin. Invest. Drugs 17 (2008) 413-422.
23. J. Marinello, C. Marchand, B.T. Mott, A. Brain, C.J. Thomas, Y. Pommier, Comparison of Raltegravir and Elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants, Biochemistry 47 (2008) 9345-9354.
24. M.J. Buzón, J. Dalmau, M.C. Puertas, J. Puig, B. Clotet, J. Martinez-Picado, The HIV-1 integrase genotype strongly predicts Raltegravir susceptibility but not viral fitness of primary virus isolates, AIDS 24 (2010) 5-7.
25. J.A. Grobler, K. Stillmock, M.D. Miller, D.J. Hazuda, Mechanism by which the HIV integrase active-site mutation N155H confers resistance to Raltegravir, Antivir. Ther. 13 (3) (2008) A41.
26. Y. Goldgur, R. Craigie, G.H. Cohen, T. Fujiwara, T. Yoshinaga, T. Fujishita, H. Suginoto, T. Endo, H. Murai, D.R. Davies, Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 13040-13043.
27. S. Hare, S.S. Gupta, E. Valkov, A. Engelman, P. Cherepanov, Retroviral intasome assembly and inhibition of DNA strand transfer, Nature 464 (2010) 232-236.
28. N.C. Fitzkee, J.E. Masse, Y. Shen, D.R. Davies, A. Bax, Solution conformation and dynamics of the HIV-1 integrase core domain, J. Biol. Chem. 285 (2010) 18072-18084.
29. C.A. Sotriffer, H. Ni, J.A. McCammon, HIV-1 integrase inhibitor interactions at the active site: prediction of binding modes unaffected by crystal packing, J. Am. Chem. Soc. 122 (2000) 6136-6137. (Pubitemid 30451130)
30. G.M. Keseru, I. Kolossvary, Fully flexible low-mode docking: application to induced fit in HIV integrase, J. Am. Chem. Soc. 123 (2001) 12708-12709. (Pubitemid 33140408)
31. R.D. Lins, A. Adesokan, T.A. Soares, J.M. Briggs, Investigations on human immunodeficiency virus type 1 integrase/DNA binding interactions via molecular dynamics and electrostatics calculations, Pharmacol. Ther. 85 (2000) 123-131.
32. A. Brigo, K.W. Lee, G.I. Mustata, J.M. Briggs, Comparison of multiple molecular dynamics trajectories calculated for the drug-resistant HIV-1 integrase T66I/M154I catalytic domain, Biophys. J. 88 (2005) 3072-3082. (Pubitemid 40586562)
33. M.C. Lee, J. Deng, J.M. Briggs, Y. Duan, Large-scale conformational dynamics of the HIV-1 integrase core domain and its catalytic loop mutants, Biophys. J. 88 (2005) 3133-3146. (Pubitemid 40586567)
34. J.R. Schames, R.H. Henchman, J.S. Siegel, C.A. Sotriffer, H.H. Ni, J.A. McCammon, Discovery of a novel binding trench in HIV integrase, J. Med. Chem. 47 (2004) 1879-1881.
35. H.H. Ni, C.A. Sotriffer, J.A. McCammon, Ordered water and ligand mobility in the HIV-1 integrase-5CITEP complex: a molecular dynamics study, J. Med. Chem. 44 (2001) 3043-3047.
36. M.L. Barreca, K.W. Lee, A. Chimirri, J.M. Briggs, Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor: mechanism for inhibition and drug resistance, Biophys. J. 84 (2003) 1450-1463. (Pubitemid 36322914)
37. A. Brigo, K.W. Lee, E. Fogolari, G.I. Mustata, J.M. Briggs, Comparative molecular dynamics simulations of HIV-1 integrase and the T66I/M154I mutant: binding modes and drug resistance to a diketo acid inhibitor, Proteins: Struct. Funct. Bioinform. 59 (2005) 723-741. (Pubitemid 40695848)
38. N. Nunthaboot, S. Pianwanit, V. Parasuk, J.O. Ebalunode, J.M. Briggs, S. Kokpol, Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations of HIV-1 integrase/inhibitor complexes, Biophys. J. 93 (2007) 3613-3626. (Pubitemid 350190824)
39. C.N. Aleves, S. Marti, R. Castillo, J. Andres, V. Moliner, E. Inaki Tunon, A. Silla, Quantum mechanic/molecular mechanic study of the wild-type and N155S mutant hiv-1 integrase complexed with diketo acid, Biophys. J. 94 (2008) 2443-2451.
40. C.N. Aleves, S. Marti, R. Castilio, J. Andres, V. Moliner, Inaki Tunon, E.A. Silla, Quantum mechanics/molecular mechanic study of the protein - ligand interaction for inhibitors of HIV-1 integrase, Chem. Eur. J. 13 (2007) 7715-7724.
41. C.N. Aleves, S. Marti, R. Castilio, J. Andres, V. Moliner, Inaki Tunon, E. Silla, Calculation of binding energy using BLYP/MM for HIV-1 integrase complexed with the S-1360 and two analogues, Bioorg. Med. Chem. 15 (2007) 3818-3824. (Pubitemid 46635135)
42. M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery Jr., R.E. Stratmann, J.C. Burant, S. Dapprich, J.M. Millam, A.D. Daniels, K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C.S. Adamo Clifford, J. Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui, K. Morokuma, P. Salvador, J.J. Dannenberg, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J. Cioslowski, J.V. Ortiz, A.G. Baboul, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, J.L. Andres, C. Gonzalez, M. Head-Gordon, E.S. Replogle, J.A. Pople, Gaussian 98, Gaussian, Inc., Pittsburgh, PA, 2001.
43. Y. Goldgur, F. Dyda, A.B. Hickman, T.M. Jenkins, R. Craigie, D.R. Davis, Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium, Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 9150-9154. (Pubitemid 28506200)
44. S. Maignan, J.P. Guilloteau, Q. Zhou-Liu, C. Clement-Mella, V. Mikol, Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases, J. Mol. Biol. 282 (1998) 359-368.
45. C.L. Brooks, R.E. Bruccoleri, B.D. Olafson, D.J. States, S. Swaminathan, M. Karplus, CHARMM: a program for macromolecular energy minimization, and dynamics calculations, J. Comput. Chem. 4 (1983) 187-217.
46. A.D. MacKerell, D. Bashford, M. Bellott, R.L. Dunbrack, J.D. Evanseck, M.J. Field, S. Fischer, J. Gao, H. Guo, S. Ha, D. Joseph-McCarthy, L. Kuchnir, K. Kuczera, F.T.K. Lau, C. Mattos, S. Michnick, T. Ngo, D.T. Nguyen, B. Prodhom, W.E. Reiher, B. Roux, M. Schlenkrich, J.C. Smith, R. Stote, J. Straub, M. Watanabe, J. Wiorkiewicz-Kuczera, D. Yin, M. Karplus, All-atom empirical potential for molecular modelling and dynamics studies of proteins, J. Phys. Chem. B 102 (1998) 3586-3616.
47. V.Z. Spassov, L. Yan, A fast and accurate computational approach to protein ionization, Protein Sci. 17 (2008) 1955-1970.
48. W.L. Jorgensen, J. Chandrasekhar, J.D. Madura, R.W. Impey, M.L. Klein, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys. 79 (1983) 926-935.
49. C.L. Brooks, M. Karplus, Solvent effects on protein motion and protein effects on solvent motion - dynamics of the active-site region of lysozyme, J. Mol. Biol. 208 (1989) 159-181.
50. M. Huang, W.G. Richards, G.H. Grant, Diketo acid HIV-1 integrase Inhibitors: an ab initio study, J. Phys. Chem. A 109 (2005) 5198-5202.
51. M. Woodruff, J.B. Plya, Pyrazolidine-3, 5-diones with heterocyclic substituents. IV. Ionization constants, Aust. J. Chem. 28 (1975) 1583-1587.
52. J. Wielens, S.J. Headey, D. Jeevarajah, D.I. Rhodes, J. Deadman, D.K. Chalmers, M.J. Scanlon, M.W. Parker, Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site, FEBS Lett. 584 (2010) 1455-1462.
53. J.S. Wai, M.S. Egbertson, L.S. Payne, T.E. Fisher, M.W. Embrey, L.O. Tran, J.Y. Melamed, H.M. Langford, J.P. Guare Jr., L. Zhuang, V.E. Grey, J.P. Vacca, M.K. Holloway, A.M. Naylor-Olsen, D.J. Hazuda, P.J. Felock, A.L. Wolfe, K.A. Stillmock, W.A. Schleif, L.J. Gabryelski, D.S. Young, 4-Aryl-2,4- dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells, J. Med. Chem. 43 (2000) 4923-4926. (Pubitemid 32039013)