Synthesis, Molecular Modelling and Biological Studies of 3-hydroxypyrane- 4-one and 3-hydroxy-pyridine-4-one Derivatives as HIV-1 Integrase Inhibitors

Author(s): Hajar Sirous, Afshin Fassihi*, Simone Brogi*, Giuseppe Campiani, Frauke Christ, Zeger Debyser, Sandra Gemma, Stefania Butini, Giulia Chemi, Alessandro Grillo, Rezvan Zabihollahi, Mohammad R. Aghasadeghi, Lotfollah Saghaie, Hamid R. Memarian.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 7 , 2019

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Abstract:

Background: Despite the progress in the discovery of antiretroviral compounds for treating HIV-1 infection by targeting HIV integrase (IN), a promising and well-known drug target against HIV-1, there is a growing need to increase the armamentarium against HIV, for avoiding the drug resistance issue.

Objective: To develop novel HIV-1 IN inhibitors, a series of 3-hydroxy-pyrane-4-one (HP) and 3- hydroxy-pyridine-4-one (HPO) derivatives have been rationally designed and synthesized.

Methods: To provide a significant characterization of the novel compounds, in-depth computational analysis was performed using a novel HIV-1 IN/DNA binary 3D-model for investigating the binding mode of the newly conceived molecules in complex with IN. The 3D-model was generated using the proto-type foamy virus (PFV) DNA as a structural template, positioning the viral polydesoxyribonucleic chain into the HIV-1 IN homology model. Moreover, a series of in vitro tests were performed including HIV-1 activity inhibition, HIV-1 IN activity inhibition, HIV-1 IN strand transfer activity inhibition and cellular toxicity.

Results: Bioassay results indicated that most of HP analogues including HPa, HPb, HPc, HPd, HPe and HPg, showed favorable inhibitory activities against HIV-1-IN in the low micromolar range. Particularly halogenated derivatives (HPb and HPd) offered the best biological activities in terms of reduced toxicity and optimum inhibitory activities against HIV-1 IN and HIV-1 in cell culture.

Conclusion: Halogenated derivatives, HPb and HPd, displayed the most promising anti-HIV profile, paving the way to the optimization of the presented scaffolds for developing new effective antiviral agents.

Keywords: 3-hydroxy-pyrane-4-one, 3-hydroxy-pyridine-4-one, halogenated derivatives, HIV-1 IN inhibitors (HIV-1 INIs), molecular modelling, anti-HIV agents.

[1]
WHO Fact Sheet No 360 Updated November 2016. Available at: http://www.who.int/mediacentre/factsheets/fs360/en/ Accessed 8 January 2018.
[2]
FDA (2017) Antiretroviral drugs used in the treatment of HIV infection. Available at: https://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm Accessed 8 January 2018.
[3]
Dayam, R.; Al-Mawsawi, L.Q.; Neamati, N. HIV-1 integrase inhibitors: An emerging clinical reality. Drugs R D., 2007, 8, 155-168.
[4]
Dubey, S.; Satyanarayana, Y.D.; Lavania, H. Development of integrase inhibitors for treatment of AIDS: An overview. Eur. J. Med. Chem., 2007, 42, 1159-1168.
[5]
Debyser, Z.; Cherepanov, P.; Van Maele, B.; De Clercq, E.; Witvrouw, M. In search of authentic inhibitors of HIV-1 integration. Antivir. Chem. Chemother., 2002, 13, 1-15.
[6]
Chiu, T.K.; Davies, D.R. Structure and function of HIV-1 integrase. Curr. Top. Med. Chem., 2004, 4, 965-977.
[7]
Pommier, Y.; Johnson, A.A.; Marchand, C. Integrase inhibitors to treat HIV/AIDS. Nat. Rev. Drug Discov., 2005, 4, 236-248.
[8]
Neamati, N.; Lin, Z.; Karki, R.G.; Orr, A.; Cowansage, K.; Strumberg, D.; Pais, G.C.; Voigt, J.H.; Nicklaus, M.C.; Winslow, H.E.; Zhao, H.; Turpin, J.A.; Yi, J.; Skalka, A.M.; Burke, T.R. Jr.; Pommier, Y. Metal-dependent inhibition of HIV-1 integrase. J. Med. Chem., 2002, 45, 5661-5670.
[9]
Dyda, F.; Hickman, A.B.; Jenkins, T.M.; Engelman, A.; Craigie, R.; Davies, D.R. Crystal structure of the catalytic domain of HIV-1 integrase: Similarity to other polynucleotidyl transferases. Science, 1994, 266, 1981-1986.
[10]
McColl, D.J.; Chen, X. Strand transfer inhibitors of HIV-1 integrase: Bringing in a new era of antiretroviral therapy. Antiviral Res., 2010, 85, 101-118.
[11]
Grobler, J.A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A.S.; Wolfe, A.; Egbertson, M.; Bourgeois, M.; Melamed, J.; Wai, J.S.; Young, S.; Vacca, J.; Hazuda, D.J. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. USA, 2002, 99, 6661-6666.
[12]
Espeseth, A.S.; Felock, P.; Wolfe, A.; Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J.Y.; Young, S.; Hamill, T.; Cole, J.L.; Hazuda, D.J. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl. Acad. Sci. USA, 2000, 97, 11244-11249.
[13]
Kawasuji, T.; Fuji, M.; Yoshinaga, T.; Sato, A.; Fujiwara, T.; Kiyama, R. A platform for designing HIV integrase inhibitors. Part 2: A two-metal binding model as a potential mechanism of HIV integrase inhibitors. Bioorg. Med. Chem., 2006, 14, 8420-8429.
[14]
Johns, B.A.; Svolto, A.C. Advances in two-metal chelation inhibitors of HIV integrase. Expert Opin. Ther. Pat., 2008, 18, 1225-1237.
[15]
Kawasuji, T.; Yoshinaga, T.; Sato, A.; Yodo, M.; Fujiwara, T.; Kiyama, R. A platform for designing HIV integrase inhibitors. Part 1: 2-hydroxy-3-heteroaryl acrylic acid derivatives as novel HIV integrase inhibitor and modeling of hydrophilic and hydrophobic pharmacophores. Bioorg. Med. Chem., 2006, 14, 8430-8445.
[16]
Rowley, M. The discovery of raltegravir, an integrase inhibitor for the treatment of HIV infection. Prog. Med. Chem., 2008, 46, 1-28.
[17]
Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D.J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M.V.; Rowley, M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem., 2008, 51, 5843-5855.
[18]
Sato, M.; Kawakami, H.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Matsuzaki, Y.; Yamataka, K.; Ikeda, S.; Shinkai, H. Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors. J. Med. Chem., 2009, 52, 4869-4882.
[19]
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. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J. Virol., 2008, 82, 764-774.
[20]
Katlama, C.; Murphy, R. Dolutegravir for the treatment of HIV. Expert Opin. Investig. Drugs, 2012, 21, 523-530.
[21]
Santos, M.A.; Marques, S.M.; Chaves, S. Hydroxypyridinones as “privileged” chelating structures for the design of medicinal drugs. Coord. Chem. Rev., 2012, 256, 240-259.
[22]
Sirous, H.; Zabihollahi, R.; Aghasadeghi, M.R.; Sadat, S.M.; Saghaie, L.; Fassihi, A. 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., 2015, 24, 2195-2212.
[23]
Rostami, M.; Sirous, H.; Zabihollahi, R.; Aghasadeghi, M.R.; Sadat, S.M.; Namazi, R.; Saghaie, L.; Memarian, H.R.; Fassihi, A. Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors. Med. Chem. Res., 2015, 24, 4113-4127.
[24]
Kawasuji, T.; Johns, B.A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J. Med. Chem., 2012, 55, 8735-8744.
[25]
Marchand, C.; Zhang, X.; Pais, G.C.; Cowansage, K.; Neamati, N.; Burke, T.R. Jr.; Pommier, Y. Structural determinants for HIV-1 integrase inhibition by beta-diketo acids. J. Biol. Chem., 2002, 277, 12596-12603.
[26]
DeAnda, F.; Hightower, K.E.; Nolte, R.T.; Hattori, K.; Yoshinaga, T.; Kawasuji, T.; Underwood, M.R. Dolutegravir interactions with HIV-1 integrase-DNA: Structural rationale for drug resistance and dissociation kinetics. PLoS One, 2013, 8e77448
[27]
Cappelli, A.; Manini, M.; Valenti, S.; Castriconi, F.; Giuliani, G.; Anzini, M.; Brogi, S.; Butini, S.; Gemma, S.; Campiani, G.; Giorgi, G.; Mennuni, L.; Lanza, M.; Giordani, A.; Caselli, G.; Letari, O.; Makovec, F. Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds. Eur. J. Med. Chem., 2013, 63, 85-94.
[28]
Giovani, S.; Penzo, M.; Brogi, S.; Brindisi, M.; Gemma, S.; Novellino, E.; Savini, L.; Blackman, M.J.; Campiani, G.; Butini, S. Rational design of the first difluorostatone-based PfSUB1 inhibitors. Bioorg. Med. Chem. Lett., 2014, 24, 3582-35866.
[29]
Gemma, S.; Brogi, S.; Patil, P.R.; Giovani, S.; Lamponi, S.; Cappelli, A.; Novellino, E.; Brown, A.; Higgins, M.K.; Mustafa, K.; Szestak, T.; Craig, A.G.; Campiani, G.; Butini, S.; Brindisi, M. From (+)-epigallocatechin gallate to a simplified synthetic analogue as a cytoadherence inhibitor for P. falciparum. Rsc Adv., 2014, 4, 4769-4781.
[30]
Brogi, S.; Giovani, S.; Brindisi, M.; Gemma, S.; Novellino, E.; Campiani, G.; Blackman, M.J.; Butini, S. In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors. J. Mol. Graph. Model., 2016, 64, 121-130.
[31]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47, 1739-1749.
[32]
Glide. Version 5.7; Schrödinger, LLC: New York, NY, 2011.
[33]
Schrödinger, Suite. 2011 QM-Polarized Ligand Docking protocol: Glide. Version 5.7. Schrödinger, LLC, New York, NY,2011; Jaguar. Version 7.8. Schrödinger, LLC, New York, NY,2011; QSite. Version 5.7; Schrödinger, LLC: New York, NY, 2011.
[34]
Paolino, M.; Brindisi, M.; Vallone, A.; Butini, S.; Campiani, G.; Nannicini, C.; Giuliani, G.; Anzini, M.; Lamponi, S.; Giorgi, G.; Sbardella, D.; Ferraris, D.M.; Marini, S.; Coletta, M.; Palucci, I.; Minerva, M.; Delogu, G.; Pepponi, I.; Goletti, D.; Cappelli, A.; Gemma, S.; Brogi, S. Development of potent inhibitors of the mycobacterium tuberculosis virulence factor ZMP1 and evaluation of their effect on mycobacterial survival inside macrophages. ChemMedChem, 2018, 13, 422-430.
[35]
Brindisi, M.; Gemma, S.; Kunjir, S.; Di Cerbo, L.; Brogi, S.; Parapini, S.; D’Alessandro, S.; Taramelli, D.; Habluetzel, A.; Tapanelli, S.; Lamponi, S.; Novellino, E.; Campiani, G.; Butini, S. Synthetic spirocyclic endoperoxides: New antimalarial scaffolds. MedChemComm, 2015, 6, 357-362.
[36]
Brindisi, M.; Brogi, S.; Relitti, N.; Vallone, A.; Butini, S.; Gemma, S.; Novellino, E.; Colotti, G.; Angiulli, G.; Di Chiaro, F.; Fiorillo, A.; Ilari, A.; Campiani, G. Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking. Sci. Rep., 2015, 5, 9705.
[37]
Gasser, A.; Brogi, S.; Urayama, K.; Nishi, T.; Kurose, H.; Tafi, A.; Ribeiro, N.; Desaubry, L.; Nebigil, C.G. Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1. PLoS One, 2015, 10e0121027
[38]
Brogi, S.; Butini, S.; Maramai, S.; Colombo, R.; Verga, L.; Lanni, C.; De Lorenzi, E.; Lamponi, S.; Andreassi, M.; Bartolini, M.; Andrisano, V.; Novellino, E.; Campiani, G.; Brindisi, M.; Gemma, S. Disease-modifying Anti-Alzheimer’s drugs: Inhibitors of human cholinesterases interfering with beta-amyloid aggregation. CNS Neurosci. Ther., 2014, 20, 624-632.
[39]
Brogi, S.; Fiorillo, A.; Chemi, G.; Butini, S.; Lalle, M.; Ilari, A.; Gemma, S.; Campiani, G. Structural characterization of Giardia duodenalis thioredoxin reductase (gTrxR) and computational analysis of its interaction with NBDHEX. Eur. J. Med. Chem., 2017, 135, 479-490.
[40]
QikProp. Version 3.4; Schrödinger, LLC: New York, NY, 2011.
[41]
P450. Site of Metabolism Prediction. Version 1.1; Schrödinger, LLC: New York, NY, 2011.
[42]
Gemma, S.; Camodeca, C.; Sanna, C.S.; Joshi, B.P.; Bernetti, M.; Moretti, V.; Brogi, S.; Bonache de Marcos, M.C.; Savini, L.; Taramelli, D.; Basilico, N.; Parapini, S.; Rottmann, M.; Brun, R.; Lamponi, S.; Caccia, S.; Guiso, G.; Summers, R.L.; Martin, R.E.; Saponara, S.; Gorelli, B.; Novellino, E.; Campiani, G.; Butini, S. Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: Further structure-activity relationships, in vivo studies, and preliminary toxicity profiling. J. Med. Chem., 2012, 55, 6948-6967.
[43]
Debyser, Z.; Cherepanov, P.; Pluymers, W.; De Clercq, E. Assays for the evaluation of HIV-1 integrase inhibitors. Methods Mol. Biol., 2001, 160, 139-155.
[44]
Christ, F.; Busschots, K.; Hendrix, J.; McNeely, M.; Engelborghs, Y.; Debyser, Z. Assays for Evaluation of HIV-1 Integrase Enzymatic Activity; DNA Binding, and Cofactor Interaction, 2011.
[45]
Hwang, Y.; Rhodes, D.; Bushman, F. Rapid microtiter assays for poxvirus topoisomerase, mammalian type IB topoisomerase and HIV-1 integrase: Application to inhibitor isolation. Nucleic Acids Res., 2000, 28, 4884-4892.
[46]
Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; Declercq, E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods, 1988, 20, 309-321.
[47]
Ellis, B.L.; Duhme, A.K.; Hider, R.C.; Hossain, M.B.; Rizvi, S.; van der Helm, D. Synthesis, physicochemical properties, and biological evaluation of hydroxypyranones and hydroxypyridinones: Novel bidentate ligands for cell-labeling. J. Med. Chem., 1996, 39, 3659-3670.
[48]
Ma, Y.; Luo, W.; Quinn, P.J.; Liu, Z.; Hider, R.C. Design, synthesis, physicochemical properties, and evaluation of novel iron chelators with fluorescent sensors. J. Med. Chem., 2004, 47, 6349-6362.
[49]
Becker, H.D. The conversion of kojic acid into comenaldehyde and comenic acid. Acta Chem. Scand., 1962, 16, 78-82.
[50]
Lindgren, B.O.; Nilsson, T. preparation of carboxylic acids from aldehydes (including hydroxylated benzaldehydes) by oxidation with chlorite. Acta Chem. Scand., 1973, 27, 888-890.
[51]
Sheehan, J.C.; Preston, J.; Cruickshank, P.A. A rapid synthesis of oligopeptide derivatives without isolation of intermediates. J. Am. Chem. Soc., 1965, 87, 2492-2493.
[52]
Puerta, D.T.; Mongan, J.; Tran, B.L.; McCammon, J.A.; Cohen, S.M. Potent, selective pyrone-based inhibitors of stromelysin-1. J. Am. Chem. Soc., 2005, 127, 14148-14149.
[53]
Harris, R.L.N. Potential wool growth inhibitors. Improved syntheses of mimosine and related 4(1H)-pyridones. Aust. J. Chem., 1976, 29, 1329-1334.
[54]
Kosak, T.M.; Conrad, H.A.; Korich, A.L.; Lord, R.L. Ether cleavage re-investigated: Elucidating the mechanism of BBr3-facilitated demethylation of aryl methyl ethers. Eur. J. Org. Chem., 2015, 2015, 7460-7467.
[55]
Engelman, A.; Craigie, R. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J. Virol., 1992, 66, 6361-6369.
[56]
Kulkosky, J.; Jones, K.S.; Katz, R.A.; Mack, J.P.; Skalka, A.M. 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., 1992, 12, 2331-2338.
[57]
Valkov, E.; Gupta, S.S.; Hare, S.; Helander, A.; Roversi, P.; McClure, M.; Cherepanov, P. Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res., 2009, 37, 243-255.
[58]
Krishnan, L.; Li, X.; Naraharisetty, H.L.; Hare, S.; Cherepanov, P.; Engelman, A. Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc. Natl. Acad. Sci. USA, 2010, 107, 15910-15915.
[59]
Tang, J.; Maddali, K.; Pommier, Y.; Sham, Y.Y.; Wang, Z. Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited. Bioorg. Med. Chem. Lett., 2010, 20, 3275-3279.
[60]
Dolan, J.; Chen, A.; Weber, I.T.; Harrison, R.W.; Leis, J. Defining the DNA substrate binding sites on HIV-1 integrase. J. Mol. Biol., 2009, 385, 568-579.
[61]
Johnson, A.A.; Marchand, C.; Patil, S.S.; Costi, R.; Di Santo, R.; Burke, T.R. Jr.; Pommier, Y. Probing HIV-1 integrase inhibitor binding sites with position-specific integrase-DNA cross-linking assays. Mol. Pharmacol., 2007, 71, 893-901.
[62]
Agapkina, J.; Smolov, M.; Barbe, S.; Zubin, E.; Zatsepin, T.; Deprez, E.; Le Bret, M.; Mouscadet, J.F.; Gottikh, M. Probing of HIV-1 integrase/DNA interactions using novel analogs of viral DNA. J. Biol. Chem., 2006, 281, 11530-11540.
[63]
Adesokan, A.A.; Roberts, V.A.; Lee, K.W.; Lins, R.D.; Briggs, J.M. Prediction of HIV-1 integrase/viral DNA interactions in the catalytic domain by fast molecular docking. J. Med. Chem., 2004, 47, 821-828.
[64]
Dirac, A.M.; Kjems, J. Mapping DNA-binding sites of HIV-1 integrase by protein footprinting. Eur. J. Biochem., 2001, 268, 743-751.
[65]
Hare, S.; Vos, A.M.; Clayton, R.F.; Thuring, J.W.; Cummings, M.D.; Cherepanov, P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl. Acad. Sci. USA, 2010, 107, 20057-20062.
[66]
Hare, S.; Gupta, S.S.; Valkov, E.; Engelman, A.; Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature, 2010, 464, 232-236.
[67]
Hare, S.; Smith, S.J.; Metifiot, M.; Jaxa-Chamiec, A.; Pommier, Y.; Hughes, S.H.; Cherepanov, P. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol. Pharmacol., 2011, 80, 565-572.
[68]
Available at: http://mordred.bioc.cam.ac.uk/~rapper/rampage.php Accessed June 2017.
[69]
Lovell, S.C.; Davis, I.W.; Arendall, W.B., III; de Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Calpha geometry: Phi, psi and Cbeta deviation. Proteins, 2003, 50, 437-450.
[70]
Luthy, R.; Bowie, J.U.; Eisenberg, D. Assessment of protein models with three-dimensional profiles. Nature, 1992, 356, 83-85.
[71]
Lins, R.D.; Adesokan, A.; Soares, T.A.; Briggs, J.M. Investigations on human immunodeficiency virus type 1 integrase/DNA binding interactions via molecular dynamics and electrostatics calculations. Pharmacol. Ther., 2000, 85, 123-131.
[72]
Illingworth, C.J.R.; Morris, G.M.; Parkes, K.E.B.; Snell, C.R.; Reynolds, C.A. Assessing the role of polarization in docking. J. Phys. Chem. A, 2008, 112, 12157-12163.
[73]
Cho, A.E.; Guallar, V.; Berne, B.J.; Friesner, R. Importance of accurate charges in molecular docking: Quantum mechanical/molecular mechanical (QM/MM) approach. J. Comput. Chem., 2005, 26, 915-931.
[74]
Agrawal, A.; DeSoto, J.; Fullagar, J.L.; Maddali, K.; Rostami, S.; Richman, D.D.; Pommier, Y.; Cohen, S.M. Probing chelation motifs in HIV integrase inhibitors. Proc. Natl. Acad. Sci. USA, 2012, 109, 2251-2256.
[75]
Metifiot, M.; Marchand, C.; Maddali, K.; Pommier, Y. Resistance to integrase inhibitors. Viruses, 2010, 2, 1347-1366.
[76]
Pearlman, D.A.; Charifson, P.S. Are free energy calculations useful in practice? A comparison with rapid scoring functions for the p38 MAP kinase protein system. J. Med. Chem., 2001, 44, 3417-3423.
[77]
Taylor, R.D.; Jewsbury, P.J.; Essex, J.W. A review of protein-small molecule docking methods. J. Comput. Aided Mol. Des., 2002, 16, 151-166.
[78]
Kuhn, B.; Kollman, P.A. Binding of a diverse set of ligands to avidin and streptavidin: An accurate quantitative prediction of their relative affinities by a combination of molecular mechanics and continuum solvent models. J. Med. Chem., 2000, 43, 3786-3791.
[79]
Huang, N.; Kalyanaraman, C.; Irwin, J.J.; Jacobson, M.P. Physics-based scoring of protein-ligand complexes: Enrichment of known inhibitors in large-scale virtual screening. J. Chem. Inf. Model., 2006, 46, 243-253.
[80]
Liu, Z.D.; Piyamongkol, S.; Liu, D.Y.; Khodr, H.H.; Lu, S.L.; Hider, R.C. Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones: Novel iron chelators with enhanced pFe3+ values. Bioorg. Med. Chem., 2001, 9, 563-573.
[81]
Billamboz, M.; Suchaud, V.; Bailly, F.; Lion, C.; Demeulemeester, J.; Calmels, C.; Andreola, M.L.; Christ, F.; Debyser, Z.; Cotelle, P. 4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel class of HIV-1 integrase inhibitors. ACS Med. Chem. Lett., 2013, 4, 606-611.


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Article Details

VOLUME: 15
ISSUE: 7
Year: 2019
Page: [755 - 770]
Pages: 16
DOI: 10.2174/1573406415666181219113225

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