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Docking studies of some 5-hydroxypyridine-4-one derivatives: evaluation of integrase and ribonuclease H domain of reverse transcriptase as possible targets for anti-HIV-1 activity

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Abstract

Anti-HIV-1 activity of a series of 5-hydroxypyridine-4-ones was evaluated using single-round HIV-1 infection assay. The first detailed molecular binding models for this scaffold interacting with the two metal-dependent viral enzyme in the retroviral life cycle, integrase, and RNase H were investigated. Docking models suggest that the chelating functionalities of the compounds interact with metal ions in a relatively hydrophilic region, anchoring the inhibitor onto the protein surface, whereas the lipophilic moieties fit in the hydrophobic cavities near the active site. Based on the obtained results, binding affinity of the molecules to the active site of both enzymes is strongly influenced by the presence of aromatic substituents or hydrophobic moieties on the main scaffold explaining the stronger and more effective in silico interactions of the 5-benzyloxy derivatives with protein-metal complex compared with free 5-hydroxyl derivatives. These findings may be useful information for the development of novel IN/RNase H dual inhibitors.

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References

  • Andreola ML (2004) Closely related antiretroviral agents as inhibitors of two HIV-1 enzymes, ribonuclease H and integrase: killing two birds with one stone. Curr Pharm Des 10:3713–3723

    Article  CAS  PubMed  Google Scholar 

  • AutoDock Tools, http://www.autodock.scripps.edu/resources/adt/index_html

  • Barral K, Balzarini J, Neyts J, De Clercq E, Hider RC, Camplo M (2006) Synthesis and antiviral evaluation of cyclic and acyclic 2-methyl-3-hydroxy-4-pyridinone nucleoside derivatives. J Med Chem 49:43–50

    Article  CAS  PubMed  Google Scholar 

  • Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vezinet-Brun F, Rouzioux C, Rozenbaum W, Mon-tagnier L (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220:868–871

    Article  PubMed  Google Scholar 

  • Budihas S, Gorshkova I, Gaidamakov S, Wamiru A, Bona M, Parniak M, Crouch R, McMahon J, Beutler J, Le Grice S (2005) Selective inhibition of HIV-1 reverse transcriptase-associated ribonu-clease H activity by hydroxylated tropolones. Nucleic Acids Res 33:1249–1256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen X, Tsiang M, Yu F, Hung M, Jones GS, Zeynalzadegan A, Qi X, Jin H, Kim CU, Swaminathan S, Chen JM (2008) Modeling, analysis, and validation of a novel HIV integrase structure provide insights into the binding modes of potent integrase inhibitors. J Mol Biol 380:504–519

    Article  CAS  PubMed  Google Scholar 

  • Chesney M (2003) Adherence to HAART regimens. AIDS Patient Care STDs 17:169–177

    Article  PubMed  Google Scholar 

  • Chiu TK, Davies DR (2004) Structure and function of HIV-1 integrase. Curr Top Med Chem 4:965–977

    Article  CAS  PubMed  Google Scholar 

  • Davies JF II, Hostomska Z, Hostomsky Z, Jordan SR, Matthews DA (1991) Crystal structure of the ribonuclease H domain of HIV-1 reverse transcriptase. Science 252:88–95

    Article  CAS  PubMed  Google Scholar 

  • De Clercq E (2010) Antiretroviral drugs. Curr Opin Pharmacol 10:507–515

    Article  PubMed  Google Scholar 

  • De Soultrait V, Lozach P, Altmeyer R, Tarrago-Litvak L, Litvak S, Andreola ML (2002) DNA aptamers derivated from HIV-1 RNase H inhibitors are strong anti-integrase agents. J Mol Biol 324:195–203

    Article  PubMed  Google Scholar 

  • Didierjean J, Isel C, Querre F, Mouscadet JF, Aubertin AM, Valnot JY, Piettre SR, Marquet R (2005) Inhibition of human immunodeficiency virus type 1 reverse transcriptase, RNase H, and integrase activities by hydroxytropolones. Antimicrob Agents Chemother 49:4884–4894

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Discovery Studio Visualizer, Release 3.5 (2012) Accelrys Software Inc San Diego, CA, USA

  • Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR (1994) Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. Science 266:1981–1986

    Article  CAS  PubMed  Google Scholar 

  • Engelman A, Craigie R (1992) Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J Virol 66:6361–6369

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 36:3219–3228

    Article  CAS  Google Scholar 

  • Grobler JA, Stillmock K, Hu B, Witmer M, Felock P, Espeseth AS, Wolfe A, Egbertson M, Bourgeois M, Melamed J, Wai JS, Young S, Vacca J, Hazuda DJ (2002) Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc Natl Acad Sci USA 99:6661–6666

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P (2010) Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464:232–236

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haren L, Ton-Hoang B, Chandler M (1999) Integrating DNA: transposases and retroviral integrases. Ann Rev Microbiol 53:245–281

    Article  CAS  Google Scholar 

  • Himmel DM, Maegley KA, Pauly TA, Bauman JD, Das K, Dharia C, Clark ADJR, Kevin Ryan K, Hickey MJ, Love RA, Hughes SH, Bergqvist S, Arnold E (2009) Structure of HIV-1 reverse transcriptase with the inhibitor β-thujaplicinol bound at the RNase H active site. Structure 17:1625–1635

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hyperchem Hyperchem, Molecular modeling system. Hyper Cube, Inc. and Auto Desk, Inc.

  • Jacobo-Molina A, Ding J, Nanni RG, Clark AD Jr, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clarket P (1993) Crystal structure of human immunodeficiency virus type1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc Natl Acad Sci USA 90:6320–6324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Johns BA, Kawasuji T, Weatherhead JG, Taishi T, Temelkoff DP, Yoshida H, Akiyama T, Taoda Y, Murai H, Kiyama R, Fuji M, Tanimoto N, Jeffrey J, Foster SA, Yoshinaga T, Seki T, Kobayashi M, Sato A, Johnson MN, Garvey EP, Fujiwara T (2013) Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744). J Med Chem 56:5901–5916

    Article  CAS  PubMed  Google Scholar 

  • Kawasuji T, Yoshinaga T, Sato A, Yodo M, Fujiwara T, Kiyama R (2006) A platform for designing HIV integrase inhibitors. Part 1. 2-Hydroxy-3-heteroaryl acrylic acid derivatives as novel HIV integrase inhibitors and modeling of hydrophilic and hydrophobic pharmacophores. Bioorg Med Chem 14:8430–8445

    Article  CAS  PubMed  Google Scholar 

  • Kawasuji T, Johns BA, Yoshida H, Taishi T, Taoda Y, Murai H, Kiyama R, Fuji M, Yoshinaga T, Seki T, Kobayashi M, Sato A, Fujiwara T (2012) Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J Med Chem 55:8735–8744

    Article  CAS  PubMed  Google Scholar 

  • Kawasuji T, Johns BA, Yoshida H, Weatherhead JG, Akiyama T, Taish T, Taoda Y, Mikamiyama-Iwata M, Murai H, Kiyama R, Fuji M, Tanimoto N, Yoshinaga T, Seki T, Kobayashi M, Sato A, Garvey EP, Fujiwara T (2013) Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J Med Chem 56:1124–1135

    Article  CAS  PubMed  Google Scholar 

  • Kirschberg TA, Balakrishnan M, Squires NH, Barnes T, Brendza KM, Chen X, Eisenberg EJ, Jin W, Kutty N, Leavitt S, Liclican A, Liu Q, Liu X, Mak J, Perry JK, Wang M, Watkins WJ, Lansdon EB (2009) RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: design, biochemical activity, and structural information. J Med Chem 52:5781–5784

    Article  CAS  PubMed  Google Scholar 

  • Klumpp K, Hang JQ, Rajendran S, Yang Y, Derosier A, In PWK, Overton H, Parkes KEB, Cammack N, Martin JA (2003) Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors. Nucleic Acids Res 31:6852–6859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Krishnan L, Li XA, Naraharisetty HL, Hare S, Cherepanov P, Engelman A (2010) Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci USA 107:15910–15915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kulkosky J, Jones KS, Katz RA, Mack JP, Skalka AM (1992) Residues critical for retroviral integrative recombination in a region that is highly conserved among retroviral/retrotransposon integrases and bacterial insertion sequence transposases. Mol Cell Biol 12:2331–2338

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lansdon EB, Liu Q, Leavitt SA, Balakrishnan M, Perry JK, Lancaster-Moyer C, Kutty N, Liu X, Squires NH, Watkins WJ, Kirschberg TA (2011) Structural and binding analysis of pyrimidinol carboxylic acid and N-hydroxy quinazolinedione HIV-1 RNase H inhibitors. Antimicrob Agents Chemother 55:2905–2915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Madani N, Hubicki AM, Perdigoto AL, Springer M, Sodroski J (2007) Inhibition of human immunodeficiency virus envelope glycoprotein-mediated single cell lysis by low-molecular-weight antagonists of viral entry. J Virol 81:532–538

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Marchand C, Johnson AA, Karki RG, Pais GC, Zhang X, Cowansage K, Patel TA, Nicklaus MC, Burke TRJR, Pommier Y (2003) Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S). Mol Pharmacol 64:600–609

    Article  CAS  PubMed  Google Scholar 

  • Marchand C, Beutler JA, Wamiru A, Budihas S, Mollmann U, Heinisch L, Mellors JW, Le Grice SF, Pommier Y (2008) Madurahydroxylactone derivatives as dual inhibitors of human immunodeficiency virus type 1 integrase and RNase H. Antimicrob Agents Chemother 52:361–364

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Métifiot M, Marchand C, Maddali K, Pommier Y (2010) Resistance to integrase inhibitors. Viruses 2:1347–1366

    Article  PubMed Central  PubMed  Google Scholar 

  • Mohammadpour M, Sadeghi A, Fassihi A, Saghaei L, Movahedian A, Rostami M (2012) Synthesis and antioxidant evaluation of some novel ortho-hydroxypyridine-4-one iron chelators. Res Pharm Sci 7(3):171–179

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm an empirical binding free energy function. J Comp Chem 19:1639–1662

    Article  CAS  Google Scholar 

  • Moyle G, Gatell J, Perno CF, Ratanasuwan W, Schechte M, Tsoukas RC (2008) Potential for new antiretrovirals to address unmet needs in the management of HIV-1 infection. AIDS Patient Care STDs 22:459–471

    Article  PubMed  Google Scholar 

  • Neamati N, Lin Z, Karki RG, Orr A, Cowansage K, Strumberg D, Pais GC, Voigt JH, Nicklaus MC, Winslow HE, Zhao H, Turpin JA, Yi J, Skalka AM, Burke TRJR, Pommier Y (2002) Metal-dependent inhibition of HIV-1 integrase. J Med Chem 45:5661–5670

    Article  CAS  PubMed  Google Scholar 

  • Nowotny M, Yang W (2006) Stepwise analyses of metal ions in RNase H catalysis from substrate destabilization to product release. EMBO J 25:1924–1933

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • OSIRIS property explorer-Organic Chemistry portal, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland. Accessed http://www.organicchemistry.org/prog/peo/

  • Pommier Y, Johnson AA, Marchand C (2005) Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Disc 4:236–248

    Article  CAS  Google Scholar 

  • Rezaei A, Zabihollahi R, Salehi M, Moghim S, Tamizifar H, Yazdanpanahi N, Amini G (2007) Designing a non-virulent HIV-1 strain: potential implications for vaccine and experimental research. J Res Med Sci 12:227–234

    CAS  Google Scholar 

  • Rowley M (2008) The discovery of Raltegravir, an integrase inhibitor for the treatment of HIV infection. Prog Med Chem 46:1–28

    Article  CAS  PubMed  Google Scholar 

  • Sarafianos SG, Das K, Tantillo C, Clarck AD Jr, Ding J, Whitcomb JM, Boyer PL, Hughes SH, Arnold E (2001) Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J 20:1449–1461

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sato M, Kawakami H, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Matsuzaki Y, Yamataka K, Ikeda S, Shinkai H (2009) Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors. J Med Chem 52:4869–4882

    Article  CAS  PubMed  Google Scholar 

  • Schatz O, Cromme FV, Gruninger-Leitch F, Grice SFJ (1989) Point mutations in conserved amino acid residues within the C-terminal domain of HIV-1 reverse transcriptase specifically repress the RNase H function. FEBS Lett 257:311–314

  • Schultz SJ, Champoux JJ (2008) RNase H activity: structure and function in reverse transcription. Virus Res 134:86–103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Semenova EA, Johnson AA, Marchand C, Davis DA, Yarchoa R, Pommier Y (2006) Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by R-hydroxytropolones. Mol Pharmacol 69:1454–1460

    Article  CAS  PubMed  Google Scholar 

  • Shaw-Reid CA, Munshi V, Graham P, Wolfe A, Witmer M, Danzeisen R, Olsen DB, Carrol SS, Embrey M, Wai JS, Miller MD, Cole JL, Hazuda DJ (2003) Inhibition of HIV-1 ribonuclease H by a novel diketo acid, 4-[5-(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid. J Biol Chem 278:2777–2780

    Article  CAS  PubMed  Google Scholar 

  • Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, Matsuoka M (2008) Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor Elvitegravir (JTK-303/GS-9137). J Virol 82:764–774

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Su HP, Yan Y, Prasad GS, Smith RF, Daniels CL, Abeywickrema PD, Reid JC, Loughran HM, Kornienko M, Sharma S, Grobler JA, Xu B, Sardana V, Allison TJ, Williams PD, Darke PL, Hazuda DJ, Munshi S (2010) Structural basis for the inhibition of RNase H activity of HIV-1 reverse transcriptase by RNase H active site-directed inhibitors. J Virol 84:7625–7633

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Gonzalez Paz O, Hazuda DJ, Jones P, Kinzel O, Laufer R, Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, Rowley M (2008) Discovery of Raltegravir, a potent, selective orally bioavailable HIV-integrase inhititor for the treatment of HIV-AIDS infection. J Med Chem 51:5843–5855

    Article  CAS  PubMed  Google Scholar 

  • Tang J, Maddali K, Pommier Y, Sham YY, Wang Z (2010) Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: docking model revisited. Bioorg Med Chem Lett 20:3275–3279

    Article  CAS  PubMed  Google Scholar 

  • Temesgen Z, Siraj DS (2008) Raltegravir: first in class HIV integrase inhibitor. Ther Clin Risk Manage 4:493–500

    CAS  Google Scholar 

  • Tramontano E, Esposito F, Badas R, Di Santo R, Costi R, La Colla P (2005) 6-[1-(4 Fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro. Anti Viral Res 65:117–124

    Article  CAS  Google Scholar 

  • Valkov E, Gupta SS, Hare S, Helander A, Roversi P, McClure M, Cherepanov P (2009) Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res 37:243–255

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang Z, Vince R (2008a) Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketo acid functionality into delavirdine. Bioorg Med Chem 16:3587–3595

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Vince R (2008b) Synthesis of pyrimidine and quinolone conjugates as a scaffold for dual inhibitors of HIV reverse transcriptase and integrase. Bioorg Med Chem Lett 18:1293–1296

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Bennett EM, Wilson DJ, Salomon C, Vince R (2007) Rationally designed dual inhibitors of HIV reverse transcriptase and integrase. J Med Chem 50:3416–3419

    Article  CAS  PubMed  Google Scholar 

  • Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, Profeta SJR, Weiner PK (1984) A new force field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 106:765–784

    Article  CAS  Google Scholar 

  • WHO Fact Sheet No 360 Updated October 2013. Accessed http://www.who.int/mediacentre/factsheets/fs360/en/

  • Williams PD, Staas DD, Venkatraman S, Loughran HM, Ruzek RD, Booth TM, Lyle TA, Wai JS, Vacca JP, Feuston BP, Ecto LT, Flynn JA, DiStefano DJ, Hazuda DJ, Bahnck CM, Himmelberger AL, Dornadula G, Hrin RC, Stillmock KA, Witmer MV, Miller MD, Grobler JA (2010) Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold. Bioorg Med Chem Lett 20:6754–6757

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Steitz TA (1995) Recombining the structures of HIV integrase, RuvC and RNase H. Structure 3:131–134

    Article  CAS  PubMed  Google Scholar 

  • Yang CM, Cheng HY, Lin TC, Chiang LC, Lin CC (2005) Acetone, ethanol and methanol extracts of Phyllanthus urinaria inhibit HSV-2 infection in vitro. Antivir Res 6:24–30

    Article  Google Scholar 

  • Yuh IS (2011) Lysophosphatidic acid (LPA) stimulates mouse mammary epithelial cell growth. Cell Biol Int 35:875–881

    Article  CAS  PubMed  Google Scholar 

  • Zabihollahi R, Vahabpour R, Hartoonian C, Sedaghati B, Sadat SM, Soleymani M, Ranjbar M, Fassihi A, Aghasadeghi MR, Memarian HR, Salehi M (2012) Evaluation of the in vitro antiretroviral potential of some Biginelli-type pyrimidines. Acta Virol 56:11–18

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461, Isfahan, Iran

    Hajar Sirous, Lotfollah Saghaie & Afshin Fassihi

  2. Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran

    Rezvan Zabihollahi, Mohammad R. Aghasadeghi & Seyed Mehdi Sadat

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  1. Hajar Sirous
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  2. Rezvan Zabihollahi
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  3. Mohammad R. Aghasadeghi
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Sirous, H., Zabihollahi, R., Aghasadeghi, M.R. et al. Docking studies of some 5-hydroxypyridine-4-one derivatives: evaluation of integrase and ribonuclease H domain of reverse transcriptase as possible targets for anti-HIV-1 activity. Med Chem Res 24, 2195–2212 (2015). https://doi.org/10.1007/s00044-014-1289-1

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