Prediction Of The Binding Mode Of N2-phenylguanine Derivative Inhibitors To Herpes Simplex Virus Type 1 Thymidine Kinase

The probable binding mode of the herpes simplex virus thymidine kinase (HSV1 TK) N2-[substituted]-phenylguanine inhibitors is proposed. A computational experiment was designed to check some qualitative binding parameters and to calculate the interaction binding energies of alternative binding modes of N2-phenylguanines. The known binding modes of the HSV1 TK natural substrate deoxythymidine and one of its competitive inhibitors ganciclovir were used as templates. Both the qualitative and quantitative parts of the computational experiment indicated that the N2-phenylguanine derivatives bind to the HSV1 TK active site in the deoxythymidine-like binding mode. An experimental observation that N2-phenylguanosine derivatives are not phosphorylated during the interaction with the HSV1 TK gives support to the proposed binding mode.1211525Collier, L., Oxford, J., (1993) Human Virology: A Text for Students of Medicine, Dentistry and Microbiology, pp. 185-212. , Oxford University Press, OxfordRichman, D.D., (1996) Antiviral Drug Resistance, pp. 79-102. , John Wiley & Sons, ChichesterFocher, F., Hildebrand, C., Freese, S., Ciarrocchi, G., Noonan, T., Sangalli, S., Brown, N., Wright, G., (1988) J. Med. Chem., 31, p. 1496Hildebrand, C., Sandoli, D., Focher, F., Gambino, J., Ciarrochi, G., Spadari, S., Wright, G., (1990) J. Med. Chem., 33, p. 203Gambino, J., Focher, F., Hildebrand, C., Maga, G., Noonan, T., Spadari, S., Wright, G., (1992) J. Med. Chem., 35, p. 2979Brown, D.G., Visse, R., Sandhu, G., Davies, A., Rizkallah, P.J., Melitz, C., Summers, W.C., Sanderson, M.R., (1995) Nat. Struct. Biol., 10, p. 876Wild, K., Bohner, T., Aubry, A., Folkers, G., Schulz, G.E., (1995) FEBS Lett., 368, p. 289(1994) Quanta User Guide, Release 4.0, , Molecular Simulations Inc., San Diego, CA(1994) CHARMm User Guide, Release 22.3, , Molecular Simulations Inc., San Diego, CADayhoff, M.O., (1979) Atlas of Protein Sequences and Structure, 5 (3 SUPPL.), p. 345. , NBRF, Washington, DCCameleon V3.1, , Oxford Molecular Ltd., Magdalen Centre, Oxford Science Park, Sandford-on-Thames, OxfordManhold, R., Krogsgaard-Larsen, P., Timmerman, H., (1993) Methods and Principles in Medicinal Chemistry, 1. , VCH Publishers, New York, NYHansch, C., Leo, A., Hoekman, D., (1995) Exploring QSAR: Hydrophobic, Electronic, and Steric Constants, , ACS Professional Reference Book, Washington, DCGaudio, A.C., Takahata, Y., (1993) Comput. Chem., 16, p. 277Cuthbertson, A.F., Richards, W.G., (1986) J. Mol. Struct. (THEOCHEM), 134, p. 41