CALCULATION OF MOLECULAR-SURFACE AREA WITH NUMERICAL FACTORS

A simple method for the calculation of molecular surface area of small as well as large molecules is presented. The method is based on Higo & Go algorithm [J. Comput. Chem. 10, 376 (1989)] for the supermolecular volume and surface area calculations. We have verified that the average molecular surface area which intercepts the cubes located at the atomic sphere surface is linearly proportional to the side area of the cubes. We determined the proportionality factors and tested them in a system with analytically known surface area and some hydro-carbon and alcohol molecules. Good correlations between calculated surface area and log(S), where S is the aqueous molar solubility of the hydrocarbons and alcohols, have been obtained.16427728

Qsar And Molecular Graphics Analysis Of N2-phenylguanines As Inhibitors Of Herpes Simplex Virus Thymidine Kinases

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. 1531-157

Qsar Study Of Inibition By Coumarins Of Iq Induced Mutation In S. Typhimurium Ta98

Coumarin and its analogs inhibit the mutagenicity of 2-amino-3- methylimidazo[4,5-f] quinoline (IQ) in Salmonella typhimurium TA98. A quantitative structure-activity relationship (QSAR) study revealed that the antimutagenic activity of coumarins is related to the energy gap between levels one and two bellow the highest occupied molecular orbital (HOMO), εHOMO-1-εHOMO-2. The QSAR model suggests that the inhibition involves a direct interaction between the coumarins and the cytochromes CYP that activate IQ to a mutagen. © 2005 Elsevier B.V. All rights reserved.7251-3231238Skoog, K., Cooking procedures and food mutagens: A literature review (1993) Food Chemistry and Toxicology, 31, pp. 655-675Debnath, A.K., Debnath, G., Shusterman, A.J., Hansch, C., A QSAR investigation of the role of hydrophobicity in regulating mutagenicity in the ames test 1. Mutagenicity of aromatic and heteroaromatic amines in Salmonella typhimurium TA98 and TA100 (1992) Environmental and Molecular Mutagenesis, 19 (1), pp. 37-52Yamazoe, Y., Shimada, M., Kamataki, T., Kato, R., Microsomal activation of 2-amino-3-methylimidazo[4,5-f]quinoline a pyrolysate of sardine and beef extracts, to a mutagenic intermediate (1983) Cancer Research, 43 (12), pp. 5768-5774Beland, F.A., Kadlubar, F.F., Formation and persistence of arylamine DNA aducts in vivo (1985) Environmental Health Perspectives, 62, pp. 19-30Beland, F.A., Kadlubar, F.F., Metabolic activation and DNA aducts of aromatic amines and nitroaromatic hydrocarbons (1990) Chemical Carcinogenesis and Mutagenesis I, pp. 267-325. , C.S. Cooper P.L. Glover Springer BerlinDirr, A., Wild, D., Synthesis and mutagenic activity of nitro-imidazoarenes. A study on the mechanism of the genotoxicity of heterocyclic arylamines and nitroarenes (1988) Mutagenesis, 3 (2), pp. 147-152Snyderwine, E.G., Roller, P.P., Wirth, P.J., Adamson, R.H., Sato, S., Thorgeirsson, S.S., Synthesis purification and mutagenicity of 2-hydroxyamino-3- methylimidazolo[4,5-f] quinoline (1987) Carcinogenesis, 8 (7), pp. 1017-1020De Compadre, R.L.L., Debnath, A.K., Shusterman, A.J., Hansch, C., LUMO energies and hydrophobicity as determinants of mutagenicity by nitroaromatic compounds in Salmonella typhimurium (1990) Environmental and Molecular Mutagenesis, 15 (1), pp. 44-55Chen, S.-C., Wong, T.Y., Chung, K.-T., Base-pair mutation caused by four nitro-group containing aromatic amines in Salmonella typhimurium TA100, TA104, TA4001, TA4006 (1997) Mutation Research, 395 (2-3), pp. 223-227Chung, K.-T., Cerniglia, C.E., Mutagenicity of azo dyes: Structure-activity relationships (1992) Mutation Research, 277 (3), pp. 201-220Chung, K.-T., Chen, S.-C., Wong, T.Y., Wei, C.-I., Effects of benzidine and benzidine analogues on growth of bacteria including Azobacter vinelandii (1998) Environmental Toxicology and Chemistry, 17 (2), pp. 271-275Chung, K.-T., Kirkovsky, L., Kirkovsky, A., Purcell, W.P., Review of mutagenicity of monocyclic aromatic amines: Quantitative structure-activity relationships (1997) Mutation Research, 387 (1), pp. 1-16Colvin, M.E., Hatch, F.T., Felton, J.S., Chemical and biological factors affecting mutagen potency (1998) Mutation Research, 400 (1-2), pp. 479-492Felton, J.S., Knize, M.G., Hatch, F.T., Tanga, M.J., Colvin, M.E., Heterocyclic amine formation and the impact of structure on their mutagenicity (1999) Cancer Letters, 143, pp. 127-134Hatch, F.T., Colvin, M.E., Quantitative structure-activity (QSAR) relationships of mutagenic aromatic and heterocyclic amines (1997) Mutation Research, 376 (1-2), pp. 87-96Hatch, F.T., Colvin, M.E., Seidl, E.T., Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes (1996) Environmental and Molecular Mutagenesis, 27 (4), pp. 314-330Maran, U., Karelson, M., Katritzky, A.R., A comprehensive QSAR treatment of the genotoxicity of heteroaromatic and aromatic amines (1999) Quantitative Structure-activity Relationships, 18 (1), pp. 3-10Poso, A., Von Wright, A., Gynther, J., An empirical and theoretical study on mechanisms of mutagenic activity of hydrazine compounds (1995) Mutation Research, 332 (1-2), pp. 63-71Shusterman, A.J., Debnath, A.K., Hansch, C., Horn, G.W., Fronczek, F.R., Greene, A.C., Watkins, S.F., Mutagenicity of dimethyl heteroaromatic triazenes in the ames test: The role of hydrophobic and electronic effects (1989) Molecular Pharmacology, 36 (6), pp. 939-944Tuppurainen, K., A plausible mechanism for the mutagenic activity (Salmonella typhimurium TA100) of MX compounds: A formation of CG-CG+-CG radical cation by one-electron reduction (1997) SAR and QSAR in Environmental Research, 7, pp. 281-286Tuppurainen, K., Frontier orbital energies hydrophobicity and steric factors as physical QSAR descriptors of molecular mutagenicity. A review with a case study: MX compounds (1999) Chemosphere, 38 (13), pp. 3015-3030You, Z., Brezzell, M.D., Das, S.K., Espadas-Torre, M.C., Hooberman, B.H., Sinsheimer, J.E., Ortho-substituent effects on the in vitro and in vivo genotoxicity of benzidine derivatives (1993) Mutation Research, 319 (1), pp. 19-30You, Z., Brezzell, M.D., Das, S.K., Hooberman, B.H., Sinsheimer, J.E., Substituent effects on the in vitro and in vivo genotoxicity of 4-aminobiphenyl and 4-aminostilbene derivatives (1994) Mutation Research, 320 (1-2), pp. 45-58Gnerre, C., Catto, M., Leonetti, F., Weber, P., Carrupt, P.A., Altomare, C., Carotti, A., Testa, B., Inhibition of monoamine oxidases by functionalized coumarin derivatives: Biological activities, QSARs, and 3D-QSARs (2000) Journal of Medicinal Chemistry, 43 (25), pp. 4747-4758Lewis, D.F.V., Lake, B.G., Ioannides, C., Parke, D.V., Inhibition of rat hepatic aryl-hydrocarbon hydroxylase-activity by a series of 7-hydroxy coumarins-QSAR studies (1994) Xenobiotica, 24 (9), pp. 829-838Poso, A., Gynther, J., Juvonen, R., A comparative molecular field analysis of cytochrome CYP 2A5 and 2A6 inhibitors (2001) Journal of Computer-Aided Molecular Design, 15 (3), pp. 195-202Huang, L., Kashiwada, Y., Cosentino, L.M., Fan, S., Chen, C.H., McPhail, A.T., Fujioka, T., Lee, K.H., Anti-aids agents.15. Synthesis and Anti-HIV activity of dihydroseselins and related analogs (1994) Journal of Medicinal Chemistry, 37 (23), pp. 3947-3955Ishikawa, T., Chemistry of Anti HIV-1 active calophyllum coumarins (1998) Journal of Synthetic Organic Chemistry Japan, 56 (2), pp. 116-124Lunney, E.A., Hagen, S.E., Domagala, J.M., Humblet, C., Kosinski, J., Tait, B.D., Warmus, J.S., Hupe, D., A novel nonpeptide HIV-1 protease inhibitor: Elucidation of the binding mode and its application in the design of related analogs (1994) Journal of Medicinal Chemistry, 37 (17), pp. 2664-2677Martyanov, I.V., Zakharova, O.D., Sottofattori, E., Pyshnyi, D.V., Yurchenko, E.Y., Babbi, P., Mazzei, M., Litvak, S., Interaction of oligonucleotides conjugated to substituted chromones and coumarins with HIV-1 reverse transcriptase (1999) Antisense and Nucleic Acid Drug Development, 9 (5), pp. 473-480Edenharder, R., Speth, C., Decker, M., Kolodziej, H., Kayser, O., Platt, K.L., Inhibition of mutagenesis of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by coumarins and furanocoumarins, chomanones and furanochromanones (1995) Mutation Research, 345 (1-2), pp. 57-71Maenpaa, J., Sigusch, H., Raunio, H., Syngelma, T., Vuorela, P., Vuorela, H., Pelkonen, O., Differential inhibition of coumarin 7-hydroxylase activity in mouse and human liver microsomes (1993) Biochemical Pharmacology, 45 (5), pp. 1035-1042Hirano, Y., Uehara, M., Saeki, K., Kato, T., Takahashi, K., Mizutani, T., The influence of quinolines on coumarin 7-hydroxylation in bovine liver microsomes and human CYP2A6 (2002) Journal of Health Science, 48 (2), pp. 118-125Wald, R.W., Feuer, G., Molecular orbital calculations on coumarins and induction of drug-metabolizing enzymes (1971) Journal of Medicinal Chemistry, 14 (11), pp. 1081-1084Hao, N.J., Huang, M.P., Lee, H., Structure-activity relationships of anthraquinones as inhibitors of 7-ethoxycoumarin O-deethylase and mutagenicity of 2-amino-3-methylimidazo[4,5-f] quinoline (1995) Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 328 (2), pp. 183-191Yun, C.H., Jeong, H.G., Jhoun, J.W., Guengerich, F.P., Nonspecific inhibition of cytochrome-CYP activities by chlorophyllin in human and rat-liver microsomes (1995) Carcinogenesis, 16 (6), pp. 1437-1440Mohamadi, F., Richards, N.G.J., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Still, W.C., Macromodel - An integrated software system for modeling organic and bioorganic molecules using molecular mechanics (1990) Journal of Computational Chemistry, 11 (4), pp. 440-467Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, S.T., Gordon, M.S., Jensen, J.H., Koseki, S., Su, S., General atomic and molecular electronic structure system (1993) Journal of Computational Chemistry, 14 (11), pp. 1347-1363Wilderman, S.A., Crippen, G.M., Prediction of physico-chemical parameters by atomic contributions (1999) Journal of Chemical Information and Computer Sciences, 39, pp. 868-873Gaudio, A.C., Takahata, Y., Calculation of molecular-surface area with numerical factors (1992) Computers and Chemistry, 16 (4), pp. 277-284Wang, R., Fu, Y., Lai, L., A new atom-additive method for calculating partition coefficients (1997) Journal of Chemical Information and Computer Sciences, 37 (3), pp. 615-621Cambridge Soft Corporation. 2004. 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Dealkylation within an homologous series and its relation to antitumor-activity (1984) Journal of Medicinal Chemistry, 27 (7), pp. 870-874Imaoka, S., Funae, Y., Induction of cytochrome CYP isozymes in rat-liver by methyl normal-alkyl ketones and normal-alkylbenzenes effects of hydrophobicity of inducers on inducibility of cytochrome CYP (1991) Biochemical Pharmacology, 42, pp. S143-S150Iwasaki, K., Lum, P.Y., Ioannides, C., Parke, D.V., Induction of cytochrome-P-448 activity as exemplified by the O-deethylation of ethoxyresorufin effects of dose, sex, tissue and animal species (1986) Biochemical Pharmacology, 35 (21), pp. 3879-3884Al-Gailany, K.A.S., Houston, J.B., Bridges, J.W., Role of substrate lipophilicity in determining type-1 microsomal CYP binding characteristics (1978) Biochemical Pharmacology, 27 (5), pp. 783-788Sargent, N.S.E., Upshall, D.G., Bridges, J.W., The relationship between binding to cytochrome-P-450 and metabolism of normal-alkyl carbamates in isolated rat hepatocytes (1982) Biochemical Pharmacology, 31 (7), pp. 1309-1313Ichikawa, Y., Yamano, T., Fujishim, H., Relationship between interconversion of cytochrome P-450 and P-420 and its activities in hydroxylations and demethylations by P-450 oxidase systems (1969) Biochimica et Biophysica Acta, 171 (1), pp. 32-37Marques, A.D.S., Lin, C.T., Molecular complexes of IQ and 4-Hydroxy Coumarin: A mutagen-anti-mutagen system (2004) J. 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