**Author details**

Rohit Arora and Luba Tchertanov

BiMoDyM, LBPA, CNRS -ENS de Cachan, LabEx LERMIT, CEDEX Cachan, France

## **References**


> National Academy of Sciences of the United States of America 2007 May 15;104(20): 8316-21.

[21] Bujacz G, Alexandratos J, Wlodawer A. Binding of different divalent cations to the active site of avian sarcoma virus integrase and their effects on enzymatic activity.

The HIV-1 Integrase: Modeling and Beyond http://dx.doi.org/10.5772/52344 397

[22] Maignan S, Guilloteau JP, Zhou-Liu Q, Clement-Mella C, Mikol V. Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofac‐ tor: High level of similarity of the active site with other viral integrases. Journal of

[23] Molteni V, Greenwald J, Rhodes D, Hwang Y, Kwiatkowski W, Bushman FD, et al. Identification of a small-molecule binding site at the dimer interface of the HIV inte‐ grase catalytic domain. Acta Crystallographica Section D-Biological Crystallography

[24] Goldgur Y, Dyda F, Hickman AB, Jenkins TM, Craigie R, Davies DR. Three new structures of the core domain of HIV-1 integrase: An active site that binds magnesi‐

[25] Goldgur Y, Craigie R, Cohen GH, Fujiwara T, Yoshinaga T, Fujishita T, et al. Struc‐ ture of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proceedings of the National Academy of Sciences of the

[26] Greenwald J, Le V, Butler SL, Bushman FD, Choe S. The mobility of an HIV-1 inte‐ grase active site loop is correlated with catalytic activity. Biochemistry 1999 Jul

[27] Chen AP, Weber IT, Harrison RW, Leis J. Identification of amino acids in HIV-1 and avian sarcoma virus integrase subsites required for specific recognition of the long terminal repeat ends. Journal of Biological Chemistry 2006 Feb 17;281(7):4173-82.

[28] Mouscadet JF, Tchertanov L. Raltegravir: molecular basis of its mechanism of action.

[29] Mouscadet JF, Delelis O, Marcelin AG, Tchertanov L. Resistance to HIV-1 integrase inhibitors: A structural perspective. Drug Resist Updat 2010 Aug;13(4-5):139-50.

[30] Lovell S, Goryshin IY, Reznikoff WR, Rayment I. Two-metal active site binding of a Tn5 transposase synaptic complex. Nature Structural Biology 2002 Apr;9(4):278-81.

[31] Karki R, Tang Y, Nicklaus MC. Model of the HIV-1 integrase-viral DNA complex - A template for structure-based design of HIV in inhibitors. Abstracts of Papers of the

[32] Karki RG, Tang Y, Burke TR, Nicklaus MC. Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design. Journal of Com‐

Journal of Biological Chemistry 1997 Jul 18;272(29):18161-8.

Molecular Biology 1998 Sep 18;282(2):359-68.

um. ProcNatlAcadSci USA 1998 Aug 4;95(16):9150-4.

United States of America 1999 Nov 9;96(23):13040-3.

Eur J Med Res 2009 Nov 24;14 Suppl 3:5-16.

American Chemical Society 2002 Aug 18;224:U9-U10.

puter-Aided Molecular Design 2004 Dec;18(12):739-60.

2001 Apr;57:536-44.

13;38(28):8892-8.


[21] Bujacz G, Alexandratos J, Wlodawer A. Binding of different divalent cations to the active site of avian sarcoma virus integrase and their effects on enzymatic activity. Journal of Biological Chemistry 1997 Jul 18;272(29):18161-8.

National Academy of Sciences of the United States of America 2007 May 15;104(20):

[9] Guiot E, Carayon K, Delelis O, Simon F, Tauc P, Zubin E, et al. Relationship between the oligomeric status of HIV-1 integrase on DNA and enzymatic activity. Journal of

An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical

[10] Faure A, Calmels C, Desjobert C, Castroviejo M, Caumont-Sarcos A, Tarrago-Litvak L, et al. HIV-1 integrase crosslinked oligomers are active in vitro. Nucleic Acids Re‐

[11] Wang Y, Klock H, Yin H, Wolff K, Bieza K, Niswonger K, et al. Homogeneous highthroughput screening assays for HIV-1 integrase 3 '-processing and strand transfer

[12] Li M, Mizuuchi M, Burke TR, Craigie R. Retroviral DNA integration: reaction path‐ way and critical intermediates. Embo Journal 2006 Mar 22;25(6):1295-304.

[13] Asante-Appiah E, Skalka AM. Molecular mechanisms in retrovirus DNA integration.

[14] Cai ML, Huang Y, Caffrey M, Zheng RL, Craigie R, Clore GM, et al. Solution struc‐ ture of the His12 -> Cys mutant of the N-terminal zinc binding domain of HIV-1 inte‐

[15] Cai ML, Zheng RL, Caffrey M, Craigie R, Clore GM, Gronenborn AM. Solution struc‐ ture of the N-terminal zinc binding domain of HIV-1 integrase. Nature Structural Bi‐

[16] Eijkelenboom APAM, vandenEnt FMI, Vos A, Doreleijers JF, Hard K, Tullius TD, et al. The solution structure of the amino-terminal HHCC domain of HIV-2 integrase: a

[17] Eijkelenboom APAM, Sprangers R, Hard K, Lutzke RAP, Plasterk RHA, Boelens R, et al. Refined solution structure of the C-terminal DNA-binding domain of human im‐ munovirus-1 integrase. Proteins-Structure Function and Genetics 1999 Sep 1;36(4):

[18] Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, et al. Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry 1995 Aug

[19] Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR. Crystal-Struc‐ ture of the Catalytic Domain of HIV-1 Integrase - Similarity to Other Polynucleotidyl

[20] Bujacz G, Alexandratos J, ZhouLiu Q, ClementMella C, Wlodawer A. The catalytic domain of human immunodeficiency virus integrase: Ordered active site in the

Transferases. Science 1994 Dec 23;266(5193):1981-6.

F185H mutant. FEBS Letters 1996 Dec 2;398(2-3):175-8.

three-helix bundle stabilized by zinc. Current Biology 1997 Oct 1;7(10):739-46.

activities. Journal of Biomolecular Screening 2005 Aug;10(5):456-62.

grase complexed to cadmium. Protein Science 1998 Dec;7(12):2669-74.

Biological Chemistry 2006 Aug 11;281(32):22707-19.

Antiviral Research 1997 Dec;36(3):139-56.

8316-21.

Applications

396

search 2005;33(3):977-86.

ology 1997 Jul;4(7):567-77.

556-64.

8;34(31):9826-33.

	- [33] Wang LD, Liu CL, Chen WZ, Wang CX. Constructing HIV-1 integrase tetramer and exploring influences of metal ions on forming integrase-DNA complex. Biochemical and Biophysical Research Communications 2005 Nov 11;337(1):313-9.

[45] Davies DR, Goryshin IY, Reznikoff WS, Rayment I. Three-dimensional structure of the Tn5 synaptic complex transposition intermediate. Science 2000 Jul 7;289(5476):

The HIV-1 Integrase: Modeling and Beyond http://dx.doi.org/10.5772/52344 399

[46] Podtelezhnikov AA, Gao K, Bushman FD, McCammon JA. Modeling HIV-1 integrase complexes based on their hydrodynamic properties. Biopolymers 2003 Jan;68(1):

[47] Ren G, Gao K, Bushman FD, Yeager M. Single-particle image reconstruction of a tet‐ ramer of HIV integrase bound to DNA. Journal of Molecular Biology 2007 Feb

[48] Mouscadet JF, Arora R, Andre J, Lambry JC, Delelis O, Malet I, et al. HIV-1 IN alter‐ native molecular recognition of DNA induced by raltegravir resistance mutations.

[49] Tama F, Gadea FX, Marques O, Sanejouand YH. Building-block approach for deter‐ mining low-frequency normal modes of macromolecules. Proteins 2000 Oct 1;41(1):

[50] Tama F, Sanejouand YH. Conformational change of proteins arising from normal

[51] Ni X, Abdel-Azeim S, Laine E, Arora R, Osemwota O, Marcelin A-G, et al. In silico and in vitro Comparison of HIV-1 Subtypes B and CRF02\_AG Integrases Susceptibil‐ ity to Integrase Strand Transfer Inhibitors. Advances in Vilology 2012;2012:548657.

[52] Yin ZQ, Craigie R. Modeling the HIV-1 Intasome: A Prototype View of the Target of

[53] Karplus M, Kuriyan J. Molecular dynamics and protein function. Proc Natl Acad Sci

[54] Karplus M, Gao YQ, Ma J, van d, V, Yang W. Protein structural transitions and their functional role. Philos Transact A Math Phys Eng Sci 2005 Feb 15;363(1827):331-55.

[55] Gerstein M, Lesk AM, Chothia C. Structural mechanisms for domain movements in

[56] Schlitter J, Engels M, Kruger P. Targeted molecular dynamics: a new approach for searching pathways of conformational transitions. J Mol Graph 1994 Jun;12(2):84-9.

[57] Bagley RJ, Farmer JD, Kauffman SA, Packard NH, Perelson AS, Stadnyk IM. Model‐

[58] Cotelle P. Patented HIV-1 integrase inhibitors (1998-2005). Recent Pat Antiinfect

[59] Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Na‐

ing adaptive biological systems. Biosystems 1989;23(2-3):113-37.

Journal of Molecular Recognition 2009 Nov;22(6):480-94.

mode calculations. Protein Eng 2001 Jan;14(1):1-6.

proteins. Biochemistry 1994 Jun 7;33(22):6739-49.

ture Reviews Drug Discovery 2005 Mar;4(3):236-48.

U S A 2005 May 10;102(19):6679-85.

Drug Discov 2006 Jan;1(1):1-15.

Integrase Inhibitors. Viruses-Basel 2010 Dec;2(12):2777-81.

77-85.

110-20.

1-7.

9;366(1):286-94.


[45] Davies DR, Goryshin IY, Reznikoff WS, Rayment I. Three-dimensional structure of the Tn5 synaptic complex transposition intermediate. Science 2000 Jul 7;289(5476): 77-85.

[33] Wang LD, Liu CL, Chen WZ, Wang CX. Constructing HIV-1 integrase tetramer and exploring influences of metal ions on forming integrase-DNA complex. Biochemical

[34] Chen ZG, Yan YW, Munshi S, Li Y, Zugay-Murphy J, Xu B, et al. X-ray structure of simian immunodeficiency virus integrase containing the core and C-terminal domain (residues 50-293) - An initial glance of the viral DNA binding platform. Journal of

[35] Wang JY, Ling H, Yang W, Craigie R. Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein. Embo Journal

[36] Ellison V, Gerton J, Vincent KA, Brown PO. An Essential Interaction Between Dis‐ tinct Domains of Hiv-1 Integrase Mediates Assembly of the Active Multimer. Journal

[37] Faure A, Calmels C, Desjobert C, Castroviejo M, Caumont-Sarcos A, Tarrago-Litvak L, et al. HIV-1 integrase crosslinked oligomers are active in vitro. Nucleic Acids Re‐

[38] Guiot E, Carayon K, Delelis O, Simon F, Tauc P, Zubin E, et al. Relationship between the oligomeric status of HIV-1 integrase on DNA and enzymatic activity. Journal of

[39] De Luca L, Pedretti A, Vistoli G, Barreca ML, Villa L, Monforte P, et al. Analysis of the full-length integrase - DNA complex by a modified approach for DNA docking. Biochemical and Biophysical Research Communications 2003 Oct 31;310(4):1083-8.

[40] Esposito D, Craigie R. Sequence specificity of viral end DNA binding by HIV-1 inte‐ grase reveals critical regions for protein-DNA interaction. EMBO Journal 1998 Oct

[41] Fenollar-Ferrer C, Carnevale V, Raugei S, Carloni P. HIV-1 integrase-DNA interac‐ tions investigated by molecular modelling. Computational and Mathematical Meth‐

[42] Wielens J, Crosby IT, Chalmers DK. A three-dimensional model of the human immu‐ nodeficiency virus type 1 integration complex. Journal of Computer-Aided Molecu‐

[43] Michel F, Crucifix C, Granger F, Eiler S, Mouscadet JF, Korolev S, et al. Structural ba‐ sis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofac‐

[44] Gao K, Butler SL, Bushman F. Human immunodeficiency virus type 1 integrase: ar‐ rangement of protein domains in active cDNA complexes. Embo Journal 2001 Jul

and Biophysical Research Communications 2005 Nov 11;337(1):313-9.

An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical

Molecular Biology 2000 Feb 18;296(2):521-33.

of Biological Chemistry 1995 Feb 17;270(7):3320-6.

Biological Chemistry 2006 Aug 11;281(32):22707-19.

2001 Dec 17;20(24):7333-43.

Applications

398

search 2005;33(3):977-86.

1;17(19):5832-43.

2;20(13):3565-76.

ods in Medicine 2008;9(3-4):231-43.

lar Design 2005 May;19(5):301-17.

tor. EMBO J 2009 Apr 8;28(7):980-91.

	- [60] Semenova EA, Marchand C, Pommier Y. HIV-1 integrase inhibitors: Update and Per‐ spectives. Adv Pharmacol 2008;56:199-228.

[72] Grobler JA, Stillmock KA, Miller MD, Hazuda DJ. Mechanism by which the HIV in‐ tegrase active-site mutation N155H confers resistance to raltegravir. Antiviral Thera‐

The HIV-1 Integrase: Modeling and Beyond http://dx.doi.org/10.5772/52344 401

[73] Delelis O, Malet I, Na L, Tchertanov L, Calvez V, Marcelin AG, et al. The G140S mu‐ tation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Research 2009 Mar;37(4):

[74] Perryman AL, Forli S, Morris GM, Burt C, Cheng YH, Palmer MJ, et al. A Dynamic Model of HIV Integrase Inhibition and Drug Resistance. Journal of Molecular Biolo‐

[75] Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, et al. Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo. Antimicrobial

[76] Kawasuji T, Fuji M, Yoshinaga T, Sato A, Fujiwara T, Kiyama R. A platform for de‐ signing HIV integrase inhibitors. Part 2: A two-metal binding model as a potential mechanism of HIV integrase inhibitors. Bioorganic & Medicinal Chemistry 2006 Dec

[77] Allen FH. The Cambridge Structural Database: a quarter of a million crystal struc‐

[78] Tchertanov L, Mouscadet JF. Target recognition by catechols and beta-ketoenols: Po‐ tential contribution of hydrogen bonding and Mn/Mg chelation to HIV-1 integrase

[79] Arora R, Chauvot de Beauchêne I, Abdel-Azeim S, Polanski J, Laine E, Tchertanov L. Raltegravir flexibility and its impact on recognition by the HIV-1 Integrase targets.

[80] Arora R, Tchertanov L. Structural determinants of Raltegravir specific recognition by the HIV-1 Integrase. 2012. Les actes: 57-60. http://jobim2012.inria.fr/

[81] Schiavoni MM, Mack HG, Ulic SE, Della Vedova CO. Tautomers and conformers of malonamide, NH2-C(O)-CH2-C(O)-NH2: vibrational analysis, NMR spectra and ab initio calculations. Spectrochim Acta A Mol Biomol Spectrosc 2000 Jul;56A(8):

[82] Barreca ML, Iraci N, De Luca L, Chimirri A. Induced-Fit Docking Approach Provides Insight into the Binding Mode and Mechanism of Action of HIV-1 Integrase Inhibi‐

[83] Loizidou EZ, Zeinalipour-Yazdi CD, Christofides T, Kostrikis LG. Analysis of bind‐ ing parameters of HIV-1 integrase inhibitors: Correlates of drug inhibition and resist‐

ance. Bioorganic & Medicinal Chemistry 2009 Jul 1;17(13):4806-18.

tures and rising. Acta Crystallogr B 2002 Jun;58(Pt 3 Pt 1):380-8.

inhibition. Journal of Medicinal Chemistry 2007 Mar 22;50(6):1133-45.

py 2008;13(4):A41.

gy 2010 Mar 26;397(2):600-15.

Agents and Chemotherapy 2010 Jan;54(1):491-501.

Journal of Molecular Recognition 2012. Submitted

tors. Chemmedchem 2009 Sep;4(9):1446-56.

jobim\_actes\_2012\_online.pdf

1533-41.

1193-201.

15;14(24):8420-9.


[72] Grobler JA, Stillmock KA, Miller MD, Hazuda DJ. Mechanism by which the HIV in‐ tegrase active-site mutation N155H confers resistance to raltegravir. Antiviral Thera‐ py 2008;13(4):A41.

[60] Semenova EA, Marchand C, Pommier Y. HIV-1 integrase inhibitors: Update and Per‐

An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical

[61] Marchand C, Maddali K, Metifiot M, Pommier Y. HIV-1 IN Inhibitors: 2010 Update and Perspectives. Current Topics in Medicinal Chemistry 2009 Aug;9(11):1016-37.

[62] Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science

[63] Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatmentnaive HIV-1-infected individuals. J Acquir Immune DeficSyndr. 2006 Dec 15;43(5):

[64] Grobler JA, Stillmock K, Hu B, Witmer M, Felock P, Espeseth AS, et al. Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the ac‐ tive site of phosphotransferase enzymes.ProcNatlAcadSci USA. 2002 May 14;99(10):

[65] Garvey EP, Schwartz B, Gartland MJ, Lang S, Halsey W, Sathe G, et al. Potent inhibi‐ tors of HIV-1 integrase display a two-step, slow-binding inhibition mechanism which is absent in a drug-resistant T66I/M154I mutant.Biochemistry. 2009 Feb

[66] Copeland RA, Pompliano DL, Meek TD. Drug-target residence time and its implica‐

[67] Dicker IB, Terry B, Lin Z, Li Z, Bollini S, Samanta HK, et al. Biochemical analysis of HIV-1 integrase variants resistant to strand transfer inhibitors. J Biol Chem. 2008 Aug

[68] Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvite‐ gravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA com‐

[69] Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al. Sub‐ group and resistance analyses of raltegravir for resistant HIV-1 infection. New Eng‐

[70] Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. New

[71] Sichtig N, Sierra S, Kaiser R, Daumer M, Reuter S, Schulter E, et al. Evolution of ralte‐ gravir resistance during therapy. Journal of Antimicrobial Chemotherapy 2009 Jul;

tions for lead optimization.Nat Rev Drug Discov. 2006 Sep;5(9):730-9.

plexes.Antimicrob Agents Chemother. 2011 Oct;55(10):4552-9.

land Journal of Medicine 2008 Jul 24;359(4):355-65.

England Journal of Medicine 2008 Jul 24;359(4):339-54.

spectives. Adv Pharmacol 2008;56:199-228.

2000 Jan 28;287(5453):646-50.

509-15.

Applications

400

6661-6.

24;48(7):1644-53.

29;283(35):23599-609.

64(1):25-32.

	- [84] Serrao E, Odde S, Ramkumar K, Neamati N. Raltegravir, elvitegravir, and metoogra‐ vir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 2009;6:25.

[96] Tsiang M, Jones GS, Hung M, Samuel D, Novikov N, Mukund S, et al. Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation. Biochemistry. 2011 Mar 15;50(10):1567-81.

The HIV-1 Integrase: Modeling and Beyond http://dx.doi.org/10.5772/52344 403

[97] De Luca L, Ferro S, Gitto R, Barreca ML, Agnello S, Christ F, et al. Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg

[98] Tsiang M, Jones GS, Niedziela-Majka A, Kan E, Lansdon EB, Huang W, Hung M, et al. New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action.Biol

Med Chem. 2010 Nov 1;18(21):7515-21.

Chem. 2012 Jun 15;287(25):21189-203.


[96] Tsiang M, Jones GS, Hung M, Samuel D, Novikov N, Mukund S, et al. Dithiothreitol causes HIV-1 integrase dimer dissociation while agents interacting with the integrase dimer interface promote dimer formation. Biochemistry. 2011 Mar 15;50(10):1567-81.

[84] Serrao E, Odde S, Ramkumar K, Neamati N. Raltegravir, elvitegravir, and metoogra‐ vir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 2009;6:25.

An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical

[85] Espeseth AS, Felock P, Wolfe A, Witmer M, Grobler, J, Anthony N., et al.HIV-1 inte‐ grase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl. Acad. Sci. U.S.A 2000; 97:11244–49.

[86] Pandey KK., Bera S., Zahm J., Vora A, Stillmock K., Hazuda D, et al. Inhibition of hu‐ man immunodeficiency virus type 1 concerted integration by strand transfer inhibi‐ tors which recognize a transient structural intermediate. J. Virol. 2007; 81: 12189–99.

[87] Sherman PA, Dickson ML. and Fyfe JA. Human immunodeficiency virus type 1 inte‐ gration protein: DNA sequence requirements for cleaving and joining reactions. J. Vi‐

[88] Johnson AA, Santos W, Pais GCG, Marchand C, Amin, R., Burker, T. R., Jr., Verdine, G., and Pommier, Y. Integration requires a specific interaction of the donor DNA ter‐ minal 5′-cytosine with glutamine 148 of the HIV-1 integrase flexible loop. J. Biol.

[89] Johnson AA, Marchand C, Patil SS, Costi R, DiSanto R, Burke, R. R. Jr. et al. Probing HIV-1 integrase inhibitor binding sites with position-specific integrase-DNA cross‐

[90] Dicker IB, Samanta HK, Li A, Hong Y, Tian Y, Banville J et al. Changes to the HIV long terminal repeat and to HIV integrase differentially impact HIV integrase assem‐ bly, activity, and the binding of strand transfer inhibitors. J. Biol. Chem. 2008; 282:

[91] Langley D, Samanta HK, Lin Z, Walker MA, Krystal M, and Dicker IB. The Terminal (Catalytic) Adenosine of the HIV LTR Controls the Kinetics of Binding and Dissocia‐ tion of HIV Integrase Strand Transfer Inhibitors. Biochemistry 2008; 47: 13481–8.

[92] Ammar FF, Abdel-Azeim S, Zargarian L, Hobaika Z, Maroun RG, Fermandjian S Un‐ processed Viral DNA Could Be the Primary Target of the HIV-1 Integrase Inhibitor

[93] Korolev S, Agapkina Yu, Gottikh M. Clinical Use of Inhibitors of HIV-1 Integration:

[94] Pannecouque C, Pluymers W, Van Maele B, Tetz V, Cherepanov P, De Clercq E, et al. New class of HIV integrase inhibitors that block viral replication in cell culture. Curr

[95] Mazumder A, Wang S, Neamati N, Nicklaus M, Sunder S, Chen J, et al. Antiretrovi‐ ral agents as inhibitors of both human immunodeficiency virus type 1 integrase and

rol. 1992; 66: 3593–601.

Applications

402

Chem. 2006; 281,:461–7.

31186–96.

linking assays. Mol. Pharmacol. 2007; 71: 893–901.

Raltegravir. PLoS One.oS One. 2012;7(7):e40223.

Biol. 2002 Jul 23;12(14):1169-77.

Problems and Prospects. Acta Naturae 2011;3;3:12-28.

protease.J Med Chem. 1996 Jun 21;39(13):2472-81.


**Chapter 16**

**Similarities Between the Binding Sites**

Patricio Iturriaga-Vásquez and Miguel Reyes-Parada

Zebrafish (*Danio rerio*) is an animal model that is attracting increasing interest in pharmacol‐ ogy and toxicology. The relatively ease with which large numbers of individuals can be ob‐ tained and their inexpensive maintenance makes zebrafish a particularly suitable tool for drug discovery. Thus, in recent years diverse compounds have been assayed both in larval and adult specimens and changes of behavioral patterns, for instance, have been related to anxiolytic, addictive or cognitive effects. In this context, the molecular characterization of drug targets in zebrafish, comparing them to their mammalian counterparts, arises as a sub‐

Monoamine oxidase (MAO) is the main catabolic enzyme of monoamine neurotransmitters and the primary target of several clinically relevant antidepressant and antiparkinsonian drugs. In mammals, it exists in two isoforms termed MAO-A and MAO-B, which share a number of structural and mechanistic features, but differ in genetic origin, tissue localization and inhibitor selectivity. High-resolution structures of MAOs from rat and human have

> © 2013 Fierro et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 Fierro et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/35874

ject of paramount importance.

**1. Introduction**

**of Monoamine Oxidase (MAO) from**

**Different Species — Is Zebrafish**

**a Useful Model for the Discovery**

**of Novel MAO Inhibitors?**

Angelica Fierro, Alejandro Montecinos, Cristobal Gómez-Molina, Gabriel Núñez, Milagros Aldeco, Dale E. Edmondson, Marcelo Vilches-Herrera, Susan Lühr,

**Chapter 16**

**Similarities Between the Binding Sites of Monoamine Oxidase (MAO) from Different Species — Is Zebrafish a Useful Model for the Discovery of Novel MAO Inhibitors?**

Angelica Fierro, Alejandro Montecinos, Cristobal Gómez-Molina, Gabriel Núñez, Milagros Aldeco, Dale E. Edmondson, Marcelo Vilches-Herrera, Susan Lühr, Patricio Iturriaga-Vásquez and Miguel Reyes-Parada

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/35874
