Abstract
A series of novel cyclic urea molecules 5,6-dihydroxy-1,3-diazepane-2,4,7-trione as HIV-1 protease inhibitors were designed using computational techniques. The designed molecules were compared with the known cyclic urea molecules by performing docking studies, calculating their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and protein ligand interaction energy. These novel molecules were designed by substituting the P 1/P′ 1 positions (4th and 7th position of 1, 3-diazepan-2-one) with double bonded oxygens. This reduces the molecular weight and increases the bioavailability, indicating better ADME properties. The docking studies showed good binding affinity towards HIV-1 protease. The biological activity of these inhibitors were predicted by a model equation generated by the regression analysis between biological activity (log 1/K i ) of known inhibitors and their protein ligand interaction energy. The synthetic studies are in progress.
[1] A.G Tomasselli, W.J. Howe, T.K. Sawyer, A. Wlodawer and R.L. Heinrikson: “The complexities of AIDS: An assessment of the HIV protease as a Therapeutic Target”, Chimica Ogg., Vol. 9, (1991), pp. 6–27. Search in Google Scholar
[2] J.R. Huff: “HIV Protease A Novel chemotherapeutic Target for AIDS”, J. Med. Chem., Vol. 34, (1991), pp. 2305–2314. http://dx.doi.org/10.1021/jm00112a00110.1021/jm00112a001Search in Google Scholar
[3] D.W. Norbeck and D.J. Kempf: “HIV Protease Inhibitors”, Annu. Rep, Med. Chem., Vol. 26, (1991), pp. 141–160. http://dx.doi.org/10.1016/S0065-7743(08)61202-610.1016/S0065-7743(08)61202-6Search in Google Scholar
[4] C. Debouck: “The HIV-1 protease as a therapeutic target for AIDS”, AIDS Res. Hum. Retroviruses., Vol. 8, (1992), pp. 153–164. http://dx.doi.org/10.1089/aid.1992.8.15310.1089/aid.1992.8.153Search in Google Scholar PubMed
[5] R.A. Katz and A.M. Skalka: “The retroviral enzymes”, Annu. Rev. Biochem., Vol. 63, (1994), pp. 133–173. http://dx.doi.org/10.1146/annurev.bi.63.070194.00102510.1146/annurev.bi.63.070194.001025Search in Google Scholar PubMed
[6] X. Wei, S.K. Gosh, M.E. Taylor, V.A. Johnson, E.A. Emini, P. Deutsch, J.D. Lifson, S. Bonhoeffer, M.A. Nowak, B.H. Hahn, M.S. Saag and G.M. Shaw: “Viral Dynamics in Human Immunodeficiency virus type-1 infection”, Nature, Vol. 373, (1995), pp. 117–122. http://dx.doi.org/10.1038/373117a010.1038/373117a0Search in Google Scholar PubMed
[7] D.D. Ho, A.U. Neumann, A.S. Perelson, W. Chen, J.M. Leonard and M. Markowitz: “Rapid turnover of Plasma Virons and CD4 lymphocytes in HIV-1 Infection”, Nature, Vol. 373, (1995), pp. 123–126. http://dx.doi.org/10.1038/373123a010.1038/373123a0Search in Google Scholar PubMed
[8] D. Kempf, K.C. Marsh, J.F. Denissen, E. McDonald, S. Vasavanonda, C.A. Flentge, B.G. Green, L. Fino, C. H. Park, X.P. Kong, N.E. Wideburg, A. Saldivar, L. Ruiz, W.M. Kati, H.L. Sham, T. Robins, K.D. Stewart, A. Hsu, J.J. Plattner, J.M. Leonard, D.W. Norbeck: “ABT-538 is a Potent Inhibitor of Human Immunodeficiency Virus Protease with high oral Bioavailability in Humans”, Proc. Natl. Acad. Sci. U.S.A., Vol. 92, (1995), pp. 2484–2488. http://dx.doi.org/10.1073/pnas.92.7.248410.1073/pnas.92.7.2484Search in Google Scholar PubMed PubMed Central
[9] E. Rutenber, E.B. Fauman, R.J. Keenan, S. Fong, S.P. Furth., P.R. Oritiz de Montellano, D.L. DeCamp, L.M. Babe and C.S. Craik: “Structure based design of Nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease”, Proc. Natl. Acad. Sci USA, Vol. 87, (1990), pp. 6644–6648. http://dx.doi.org/10.1073/pnas.87.17.664410.1073/pnas.87.17.6644Search in Google Scholar PubMed PubMed Central
[10] D.C. Humber, N. Cammack, J. Coates, K.N. Cobley, D.C. Orr, R. Storer, G.G. Weingarten and M.P. Weir: “Penicillin Derived C2 symmetrical Dimers as Novel Inhibitors of HIV-1 Proteinase”, J. Med. Chem, Vol. 35, (1992), pp. 3080–3081. http://dx.doi.org/10.1021/jm00094a02410.1021/jm00094a024Search in Google Scholar PubMed
[11] P.Y.S. Lam, P.K. Jadhav, C.J. Eyermann, C.N. Hodge, Y. Ru, L.T. Bacheler, J.L. Meek, M.J. Otto, M.M. Rayner, Y.N. Wong, C.H. Chang, P.C. Weber, T.R. Sharpe, D.A. Jackson and S. Erickson-Viitanen: “Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease Inhibitors”, Science, Vol. 263, (1994), pp. 380–384. http://dx.doi.org/10.1126/science.827881210.1126/science.8278812Search in Google Scholar PubMed
[12] QikProp, version 2.5, Schrödinger, LLC, New York, NY, 2005. Search in Google Scholar
[13] L.Y. Han, H.H. Lin, Z.R. Li, C.J. Zheng, Z.W. Cao, B. Xie and Y.Z. Chen: “PEARLS: Program for Energetic Analysis of Receptor-Ligand System”, J. Chem. Inf. Model., Vol. 46, (2006), pp. 445–450. http://dx.doi.org/10.1021/ci050214610.1021/ci0502146Search in Google Scholar
[14] H.L. Sham, C. Zhao, K.D. Stewert, D.A. Betebenner, S. Lin, C.H. Park, X.P. Knong, W.J. Rosenbrook, T. Herrin, D. Madigan, S. Vasavaononda, N. Lyons, A. Molla, A. Saldivar, K.C. Marsh, E. McDonald, N.E. Wideburg, J.F. Platter and D.W. Norbeck: “A Novel picomolar inhibitor of Human immunodeficiency virus type-1 Protease”, J. Med. Chem., Vol. 39, (1996), pp. 392–397. http://dx.doi.org/10.1021/jm950718310.1021/jm9507183Search in Google Scholar
[15] M. Rarey, B. Karmer, T. Lengauer and G. Klebe: “A fast flexible docking method using an incremental construction algorithm”, J. Mol. Biol., Vol. 261, (1996), pp. 470–489. http://dx.doi.org/10.1006/jmbi.1996.047710.1006/jmbi.1996.0477Search in Google Scholar
[16] D. Hoffmann, B. Kramer, T. Washio, T. Steinmetzer, M. Rayer, T. Lengauer: “Two stage method for protein-ligand docking”, J. Med. Chem., Vol. 42, (1999), pp. 4422–4433. http://dx.doi.org/10.1021/jm991090p10.1021/jm991090pSearch in Google Scholar
[17] J. Wang, P.A. Kollman and I.D. Kuntz: “Flexible ligand docking: A multistep strategy approach”, Proteins, Vol. 36, (1999), pp. 1–19. http://dx.doi.org/10.1002/(SICI)1097-0134(19990701)36:1<1::AID-PROT1>3.0.CO;2-T10.1002/(SICI)1097-0134(19990701)36:1<1::AID-PROT1>3.0.CO;2-TSearch in Google Scholar
[18] P.Y.S. Lam, Yu. Ru, P.K. Jadhav, P.E. Aldrich, G.V. DeLucca, C.J. Eyermann, C.H. Chang, G. Emmet., E.R. Holler, W.F. Daneker, L. Li, P.N. Confalone, L.T. Bacheler, M.M. Rayner, R.M. Klabe, L. Shum, D.L. Winslow, D.M. Kornahouse, D.A. Jackson, S. Erickson-Viitanen and C.N. Hodge: “Cyclic HIV Protease Inhibitor: Synthesis, Conformational Analysis, P 2/P′ 2 Structure-Activity Relationship and Molecular Recognition of Cyclic Ureas”, J. Med. Chem., Vol. 39, (1996), pp. 3514–3525. http://dx.doi.org/10.1021/jm960257110.1021/jm9602571Search in Google Scholar
[19] P.K. Jadhav, P. Ala, F.J. Woerner, C.H. Chang, S.S. Garber, E.D. Anton and L.T. Bacheler: “Cyclic Urea Amides: HIV-1 Protease Inhibitors with low Nanomolar Potency against both Wild type and Protease Inhibitor Resistant Mutants of HIV”, J. Med. Chem., Vol. 40, (1997), pp. 181–191. http://dx.doi.org/10.1021/jm960586t10.1021/jm960586tSearch in Google Scholar
[20] P.K. Jadhav, F.J. Woerner, P.Y.S. Lam, C.N. Hodge, C.J. Eyermann, Hon-Wah Man, W.F. Daneker, L.T. Bacheler, M.M. Rayner, J.L. Meek, S. Erickson-Viitanen, D.A. Jackson, J.C. Calabrese, M. Schadt and C.H. Chang: “Nonpeptide Cyclic Cyanoguanidines and HIV-1 protease Inhibitors: Synthesis, Structure-Activity Relationships and X-ray Crystal Structure studies”, J. Med. Chem., Vol. 41, (1998), pp. 1446–1455. http://dx.doi.org/10.1021/jm970524i10.1021/jm970524iSearch in Google Scholar
[21] J.D. Rodgers, B.L. Johnson, H. Wang, S. Erickson-Viitanen, R.M. Klabe, L.T. Bacheler, B.C. Cordova and C.H. Chang: “Potent Cyclic Urea HIV protease inhibitors with 3-aminoindazole P 2/P′ 1 groups”, Bioorg. Med. Chem. Lett., Vol. 8, (1998), pp. 715–720. http://dx.doi.org/10.1016/S0960-894X(98)00118-810.1016/S0960-894X(98)00118-8Search in Google Scholar
[22] M. Patel, L.T. Bacheler, M.M. Rayner, B.C. Cordova, R.M. Klabe, S. Erickson Viitanen and S.P. Sitz: “The Synthesis and Evaluation of Cyclic Ureas as HIV protease inhibitors: modification of the P 1/P′ 1 groups”, Bioorg. Med. Chem.Lett., Vol. 8, (1998), pp. 823–828. http://dx.doi.org/10.1016/S0960-894X(98)00119-X10.1016/S0960-894X(98)00119-XSearch in Google Scholar
[23] M. Patel, R.F. Kaltenbach III, D.A. Nugie, R.J. Mchugh Jr, P.K. Jadhav, L.T. Bacheler, B.C. Cordova, R.M. Klabe, S. Erickson-Viitanen, S.S. Garber, C. Ried and S.P. Sitz: “The Synthesis of Symmetircal and Unsymmetrical P 1/P′ 1 Cyclic Ureas as HIV protease inhibitors”, Bioorg. Med. Chem.Lett., Vol. 8, (1998), pp. 1077–1082. http://dx.doi.org/10.1016/S0960-894X(98)00175-910.1016/S0960-894X(98)00175-9Search in Google Scholar
[24] K. Bhanuprakash, B. Irena, B. Fabio and M. Stanisalav: “Computational Design of New cyclic Urea Inhibitors for improved binding of HIV-1 Aspartic Protease”, Biochem. BioPhy. Res. Comm., Vol. 268, (2000), pp. 384–389. http://dx.doi.org/10.1006/bbrc.2000.213910.1006/bbrc.2000.2139Search in Google Scholar
[25] A.H. Thomas, J.R. Greenwood, L.L. Frye, R.B. Murphy and R.A. Friesner: “Novel high affinity p38 kinase inhibitors by virtual screening by Glide. Modeling structure and Reactivity”, WATOC-2005, 7th congress of the world association of theoretically oriented chemists. Search in Google Scholar
[26] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney: “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings”, Adv. Drug. Deliver. Rev., Vol. 23, (1997), pp. 3–25. http://dx.doi.org/10.1016/S0169-409X(96)00423-110.1016/S0169-409X(96)00423-1Search in Google Scholar
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