A Dynamic Model of HIV Integrase Inhibition and Drug Resistance

Journal of Molecular Biology

Volumn 397, Issue 2, 2010, Pages 600-615

  Perryman, Alex L ^a   Forli, Stefano ^a   Morris, Garrett M ^a   Burt, Catherine ^b   Cheng, Yuhui ^c   Palmer, Michael J ^b   Whitby, Kevin ^b   McCammon, J Andrew ^c   Phillips, Chris ^b   Olson, Arthur J ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

HIV integrase inhibitor docking; mechanisms of drug resistance; metalloprotein modeling; Relaxed Complex scheme; restrained molecular dynamics

Indexed keywords

INTEGRASE; MAGNESIUM ION; RALTEGRAVIR;

ANTIVIRAL RESISTANCE; ARTICLE; CONTROLLED STUDY; DRUG PROTEIN BINDING; ENZYME ACTIVE SITE; ENZYME CONFORMATION; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS; MOLECULAR DOCKING; MOLECULAR DYNAMICS; MOLECULAR MODEL; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN MOTIF; SOLVATION; VIRUS MUTATION; WILD TYPE;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 77649183663     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jmb.2010.01.033     Document Type: Article

References (58)

1. Summa V., Petrocchi A., Bonelli F., Crescenzi B., Donghi M., Rowley M., et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 51 (2008) 5843-5855
2. Hazuda D.J., Felock P., Witmer M., Wolfe A., Stillmock K., Miller M.D., et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287 (2000) 646-650
3. Fikkert V., Van Maele B., Vercammen J., Hantson A., Van Remoortel B., Witvrouw M., et al. Development of resistance against diketo derivatives of human immunodeficiency virus type 1 by progressive accumulation of integrase mutations. J. Virol. 77 (2003) 11459-11470
4. Johns B.A., and Svolto A.C. Advances in two-metal chelation inhibitors of HIV integrase. Expert Opin. Ther. Pat. 18 (2008) 1225-1237
5. Langford H.M., Williams P.D., Homnick C.F., Vacca J.P., Felock P.J., Schleif W.A., et al. Design and synthesis of substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides, novel HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett. 18 (2008) 721-725
6. Cooper D.A., Steigbigel R.T., Gatell J.M., Rockstroh J.K., Katlama C., Nguyen B.Y., et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N. Engl. J. Med. 359 (2008) 355-365
7. Myers R.E., and Pillay D. Analysis of natural sequence variation and covariation in human immunodeficiency virus type 1 integrase. J. Virol. 82 (2008) 9228-9235
8. De Luca L., Pedretti A., Vistoli G., Barreca M.L., Villa L., Monforte P., and Chimirri A. Analysis of full-length integrase-DNA complex by a modified approach for DNA docking. Biochem. Biophys. Res. Commun. 310 (2003) 1083-1088
9. De Luca L., Vistoli G., Pedretti A., Barreca M.L., and Chimirri A. Molecular Dynamics studies of the full-length integrase-DNA complex. Biochem. Biophys. Res. Commun. 336 (2005) 1010-1016
10. Ferro S., De Luca L., Barreca M.L., Iraci N., De Grazia S., Chimirri A., et al. Docking studies on a new human immunodeficiency virus integrase-Mg-DNA complex: phenyl ring exploration and synthesis of 1H-benzylindole derivatives through fluorine substitutions. J. Med. Chem. 52 (2009) 569-573
11. Wang L.D., Liu C.L., Chen W.Z., and Wang C.X. Constructing HIV-1 integrase tetramer and exploring influences of metal ions on forming integrase-DNA complex. Biochem. Biophys. Res. Commun. 337 (2005) 313-319
12. Chen X., Tsiang M., Yu F., Hung M., Jones G.S., Chen J.M., et al. Modeling, analysis, and validation of a novel HIV integrase structure provide insights into the binding modes of potent integrase inhibitors. J. Mol. Biol. 380 (2008) 504-519
13. Loizidou E.K., Kousiappa I., Zeinalipour-Yazdi C.D., Van de Vijver D.A.M.C., and Kostrikis L.G. Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses. Biochemistry 48 (2009) 4-6
14. Savarino A. In-silico docking of HIV-1 integrase inhibitors reveals a novel drug type acting on an enzyme/DNA reaction intermediate. Retrovirology 4 (2007) 21-35
15. Barreca M.L., Iraci N., De Luca L., and Chimirri A. Induced-fit docking approach provides insight into the binding mode and mechanism of action of HIV-1 integrase inhibitors. ChemMedChem 4 (2009) 1446-1456
16. Bock C.W., Katz A.K., Markham G.D., and Glusker J.P. Manganese as a replacement for magnesium and zinc: functional comparison of the divalent ions. J. Am. Chem. Soc. 121 (1999) 7360-7372
17. Schames J.R., Henchman R.H., Siegel J.S., Sotriffer C.A., Ni H., and McCammon J.A. Discovery of a novel binding trench in HIV integrase. J. Med. Chem. 47 (2004) 1879-1881
18. Hazuda D.J., Anthony N.J., Gomez R.P., Jolly S.M., Wai J.S., Young S.D., et al. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl Acad. Sci. USA 101 (2004) 11233-11238
19. Courcot B., Firley D., Fraisse B., Becker P., Gillet J.M., Ghermani N.E., et al. Crystal and electronic structures of magnesium(II), copper(II), and mixed magnesium(II)-copper(II) complexes of quinoline half of styrylquinoline-type HIV-1 integrase inhibitors. J. Phys. Chem. B 111 (2007) 6042-6050
20. Cooper D.A., Steigbigel R.T., Gatell J.M., Rockstroh J.K., Katlama C., Nguyen B.Y., et al. BENCHMRK Study Teams: Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N. Engl. J. Med. 359 (2008) 355-365
21. Fransen S., Gupta S., Danovich R., Hazuda D., Miller M., Huang W., et al. Loss of raltegravir susceptibility in treated patients is conferred by multiple non-overlapping genetic pathways. Antivir. Ther. 13 Suppl. 3 (2008) A9
22. Charpentier C., Karmochkine M., Laureillard D., Tisserand P., Bélec L., Piketty C., et al. Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy. HIV Med. 9 (2008) 765-770
23. Delelis O., Malet I., Na L., Tchertanov L., Calvez V., Mouscadet J.F., et al. The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Res. 37 (2009) 1193-1201
24. Nakahara K., Wakasa-Morimoto C., Kobayashi M., Miki S., Noshi T., Fujiwara T., et al. Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics. Antiviral Res. 81 (2009) 141-146
25. Miller M.D., Danovich R.M., Ke Y., Witmer M., Zhao J., Harvey C., et al., on behalf of the P005 Study Team. Longitudinal analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from P005 a phase II study in treatment-experienced patients. Antivir. Ther. 13 Suppl. 3 (2008) A8
26. Fransen S., Karmochkine M., Huang W., Weiss L., Petropoulos C.J., and Charpentier C. Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of human immunodeficiency virus type 1 during virologic failure. Antimicrob. Agents Chemother. 53 (2009) 4522-4524
27. Greenwald J., Le V., Butler S.L., Bushman F.D., and Choe S. The mobility of an HIV-1 integrase active site loop is correlated with catalytic activity. Biochemistry 38 (1999) 8892-8898
28. Huey R., Morris G.M., Olson A.J., and Goodsell D.S. A semiempirical free energy force field with charge-based desolvation. J. Comput. Chem. 28 (2007) 1145-1152
29. Morris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., and Olson A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 30 (2009) 2785-2791
30. Lin J.H., Perryman A.L., Schames J.R., and McCammon J.A. Computational drug design accommodating receptor flexibility-the Relaxed Complex scheme. J. Am. Chem. Soc. 124 (2002) 5632-5633
31. Amaro R.E., Baron R., and McCammon J.A. An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J. Comput. Aided Mol. Des. 22 (2008) 693-705
32. O'Donoghue P., and Luthey-Schulten Z. Evolutionary profiles derived from the QR factorization of multiple structural alignments gives an economy of information. J. Mol. Biol. 346 (2005) 875-894
33. Roberts E., Eargle J., Wright D., and Luthey-Schulten Z. MultiSeq: unifying sequence and structure data for evolutionary analysis. BMC Bioinformatics 7 (2006) 382
34. Lu R., Limon A., Ghory H.Z., and Engelman A. Genetic analyses of DNA-binding mutants in the catalytic core domain of human immunodeficiency virus type I integrase. J. Virol. 79 (2005) 2493-2505
35. Jenkins T.M., Esposito D., Engelman A., and Craigie R. Critical contacts between HIV-1 integrase and viral DNA identified by structure-based analysis and photo-crosslinking. EMBO J. 16 (1997) 6849-6859
36. Delelis O., Thierry S., Subra F., Simon F., Malet I., Mouscadet J.F., et al. Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo. Antimicrobial Agents Chemother. 54 (2010) 491-501
37. Ceccherini-Silberstein F., Malet I., D'Arrigo R., Antinori A., Marcelin A.G., and Perno C.F. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev. 11 (2009) 17-29
38. Wiskerchen M., and Muesing M.A. Human immunodeficiency virus type I integrase: effects of mutations on viral ability to integrate, direct viral gene expression from unintegrated viral DNA templates, and sustain viral propagation in primary cells. J. Virol. 69 (1995) 376-386
39. Shin C.G., Taddeo B., Haseltine W.A., and Farnet C.M. Genetic analysis of the human immunodeficiency virus type I integrase protein. J. Virol. 68 (1994) 1633-1642
40. Gerton J.L., Ohgi S., Olsen M., Derisi J., and Brown P.O. Effects of mutations in residues near the active site of human immunodeficiency virus type I integrase on specific enzyme-substrate interactions. J. Virol. 72 (1998) 5046-5055
41. Esposito D., and Craigie R. Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein-DNA interaction. EMBO J. 17 (1998) 5832-5843
42. Goldgur Y., Craigie R., Cohen G.H., Fujiwara T., Yoshinaga T., Davies D.R., et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design. Proc. Natl Acad. Sci. USA 96 (1999) 13040-13043
43. Maignan S., Guilloteau J.P., Zhou-Liu Q., Clement-Mella C., and Mikol V. 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
44. Bujacz G., Alexandratos J., Wlodawer A., Merkel G., Andrake M., Katz R.A., and Skalka A.M. Binding of different divalent cations to the active site of avian sarcoma virus integrase and their effects on enzymatic activity. J. Biol. Chem. 272 (1997) 18161-18168
45. SYBYL 7.2, Tripos International, 1699 South Hanley Rd., St. Louis, Missouri, 63144, USA.
46. Lovell S.C., Davis I.W., Arendall III W.B., de Bakker P.I., Word J.M., Richardson D.C., et al. Structure validation by C-alpha geometry: phi, psi, and C-beta deviation. Proteins: Struct. Funct. Genet. 50 (2003) 437-450
47. Case D.A., Darden T.E., Cheatham T.E., Simmerling C.L., Ross W.S., Kollman P.A., et al. AMBER 9 (2006), University of California, San Francisco
48. Hornak V., Abel R., Okur A., Strockbine B., Roitberg A., and Simmerling C. Comparison of multiple AMBER force fields and development of improved protein backbone parameters. Proteins 65 (2006) 712-725
49. Jorgensen W.L., Chandrasekhar J., Madura J.D., Impey R.W., and Klein M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79 (1983) 926-935
50. Darden T., York D., and Pedersen L. Particle mesh Ewald-an Nlog(N) method for Ewald sums in large systems. J. Chem. Phys. 98 (1993) 10089-10092
51. Essmann U., Perera L., Berkowitz M.L., Darden T., Lee H., and Pedersen L.G. A smooth particle mesh Ewald method. J. Chem. Phys. 103 (1995) 8577-8593
52. Miyamoto S., and Kollman P.A. SETTLE: an analytical version of the SHAKE and RATTLE algorithm for rigid water models. J. Comput. Chem. 13 (1992) 952-962
53. Eastwood M.P., Hardin C., Luthey-Schulten Z., and Wolynes P.G. Evaluating protein structure-prediction schemes using energy landscape theory. IBM J. Res. Dev. 45 (2001) 475-497
54. Langley D.R., Samanta H.K., Lin Z., Walker M.A., Krystal M.R., and Dicker I.B. The terminal (catalytic) adenosine of the HIV LTR controls the kinetics of binding and dissociation of HIV integrase strand transfer inhibitors. Biochemistry 47 (2008) 13481-13488
55. Gasteiger M., and Marsili M. Iterative partial equalization of orbital electronegativity. Tetrahedron 36 (1980) 3219
56. Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Pople J.A., et al. GAUSSIAN 03 (2004), Gaussian, Inc., Wallingford, CT
57. Sanner M.F. Python: a programming language for software integration and development. J. Mol. Graphics Mod. 17 (1999) 57-61
58. DeLano W.L. The PyMOL Molecular Graphics System (2002), DeLano Scientific, Palo Alto, CA, USA. http://www.pymol.org http://www.pymol.org