A quantitative structure-activity relationship study of N2-(substituted)-phenylguanines (PHG) as inhibitors of herpes simplex virus thymidine kinase (HSV TK) was performed. The activity of a set of PHG derivatives were analyzed against the thymidine kinase of herpes simplex virus types 1 (HSV1 TK) and 2 (HSV2 TK). Classic and calculated physicochemical parameters were included in the analysis. The results showed that there is an important difference in the activity of the meta substituted PHG derivatives against HSV1 TK and HSV2 TK. The activity of the meta derivatives against HSV2 TK is influenced by a steric effect, which is not observed against HSV1 TK. The superposition of the three-dimensional structures of the active sites of HSV1 TK (crystal structure) and HSV2 TK (homology model) revealed that the amino acid Ile97 is located near the meta position in the HSV1 TK active site, whereas the amino acid Leu97 is located near the meta position in the HSV2 TK active site. This single difference in the active sites of both enzymes can explain the source of the steric effect and serves as an indication that our previously proposed binding mode for the PHG derivatives is plausible. However, another observed mutation in the active site region, Ala168 by Ser168, suggests that an alternative binding mode, similar to that of ganciclovir, could be possible. © 2000 by Elsevier Science Inc.1813341Collier, L., Oxford, J., (1993) Human Virology: A Text for Students of Medicine, Dentistry, and Microbiology, , Oxford University Press, OxfordRichman, D.D., (1996) Antiviral Drug Resistance, , John Wiley & Sons, GuilfordFocher, F., Hildebrand, C., Freese, S., Ciarrocchi, G., Noonan, T., Sangalli, S., Brown, N., Wright, G., N2-phenyldeoxyguanosine: A novel selective inhibitor of herpes simplex thymidine kinase (1988) J. Med. Chem., 31, pp. 1496-1500Hildebrand, C., Sandoli, D., Focher, F., Gambino, J., Ciarrocchi, G., Spadari, S., Wright, G., Structure-activity relationships of N2-Substituted guanines as inhibitors of HSV1 and HSV2 thymidine kinases (1990) J. Med. Chem., 33, pp. 203-206Gambino, J., Focher, F., Hildebrand, C., Maga, G., Noonan, T., Spadari, S., Wright, G., Quantitative structure-activity relationships of N2-phenylguanines as inhibtors of herpes simplex virus thymidine kinases (1992) J. Med. Chem., 35, pp. 2979-2983Hadjipavlou-Litina, D., QSAR of N2-phenylguanidines as inhibitors of herpes simplex virus-1 thymidine kinase (1995) Pharmazie, 50, pp. 796-798Hansch, C., Leo, A., Hoekman, D., (1995) Exploring QSAR: Hydrophobic, Electronic, and Steric Constants, , American Chemical Society, Washington, DCKubinyi, H., QSAR: Hansch analysis and related approaches (1993) Methods and Principles in Medicinal Chemistry, 1, pp. 21-25. , (Mannhold, R., Krogsgaard-Larsen, P., and Timmerman, H., Eds.). VCH, WeinheimGaudio, A.C., Takahata, Y., Richards, W.G., Prediction of the binding mode of N2-phenylguanines derivative inhibitors to herpes simplex virus type 1 thymidine kinase (1998) J. Comput. Aided Mol. Des., 12, pp. 15-25Sun, H., (1997), Ph.D thesis. Clark University, Worcester, MABrown, D.G., Visse, R., Sandhu, G., Davies, A., Rizkallah, P.J., Melitz, C., Summers, W.C., Sanderson, M.R., Crystal structure of the thymidine kinase from herpes simplex virus type-I in complex with deoxythymidine and ganciclovir (1995) Nat. Struct. Biol., 2, pp. 876-881Wild, K., Bohner, T., Aubry, A., Folkers, G., Schulz, G.E., The three-dimensional structure of thymidine kinase from herpes simplex virus type 1 (1995) FEBS Lett, 368, pp. 289-292Bennett, M.S., Wien, F., Champness, J.N., Batuwangala, T., Rutherford, T., Summers, W.C., Sun, H., Sanderson, M.R., Structure to 1.9 Å resolution of a complex with herpes simplex virus type-1 thymidine kinase of a novel, non substrate inhibitor: X-ray crystallographic comparison with binding of acyclovir (1999) FEBS Lett, 443, pp. 121-125Gaudio, A.C., (1998), PhD thesis. Universidade Estadual de Campinas, CampinasRichards, W.G., (1983) Quantum Pharmacology 2nd Edition, , Butterworths, LondonKarelson, M., Lobanov, V.S., Katritzky, A.R., Quantum-chemical descriptors in QSAR/QSPR studies (1996) Chem. Rev., 96, pp. 1027-1043Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J.J.P., AM1: A new general purpose quantum mechanical molecular model (1985) J. Am. Chem. Soc., 107, pp. 3902-3909Stewart, J.J.P., MOPAC: A semiempirical molecular orbital program (1990) J. Comput. Aided Mol. Des., 4, pp. 1-105Gaudio, A.C., Takahata, Y., Calculation of molecular-surface area with numerical factors (1992) Comp. Chem., 16, pp. 277-284Dayhoff, M.O., (1979) Atlas of Protein Sequences and Structure, 5 (SUPPL. 3). , NBRF, Washington, DC(1994) Cameleon, Release 3.1, , Oxford Molecular Ltd., Oxford(1994) CHARMm, Release 22.3, , Molecular Simulations, San Diego(1994) Quanta, Release 4.0, , Molecular Simulations, San DiegoSwain, M.A., Galloway, D.A., Nucleotide sequence of the herpes simplex virus type 2 thymidine kinase gene (1983) J. Virol., 46, pp. 1045-1050Kit, S., Kit, M., Qavi, H., Trkula, D., Otsuka, H., Nucleotide sequence of the herpes simplex virus type 2 (HSV-2) thymidine kinase gene and predicted amino acid sequence of thymidine kinase polypeptide and its comparison with the HSV-1 thymidine kinase gene (1983) Biochim. Biophys. Acta, 741, pp. 158-170McGeoch, D.J., Dalrymple, M.A., Davison, A.J., Dolan, A., Frame, M.C., McNab, D., Perry, L.J., Taylor, P., The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1 (1988) J. Gen. Virol., 69, pp. 1531-1574