N.Gorinchoy et al./Chem.J.Mold. 2008, 3 (1), 94-104The results are presented in Table 4: I and II are the fittings obtained over the 17 most active compounds withthree and five regression parameters, respectively, and III is a fitting received over 21 compounds that include theweakly active ones. While correlation II is somewhat better than I due to the additional two parameters, correlationIII allows one to screen and predict also weak toxicities with logLC 50> 1.4. For strong toxicity with logLC 50< 1.4correlation I is quite reasonable. This indicates the significance <strong>of</strong> the parameters <strong>of</strong> the active atom 1 in reducing thetoxicity.Table 4Regression coefficients for three types <strong>of</strong> correlation (eqs. 10, 12)Regression a 0a 1a 2a 3a 4R 2I - 7.58 14.74 1.36 - 0.94II 5.18 2.83 5.82 0.39 0.31 0.97III 1.6 3.29 6.49 0.46 0.54 0.86ConclusionsUsing the electron-conformational method we have shown that aquatic toxicity to fish is due to a specialfunctional group, the toxicophore, a combination <strong>of</strong> four atomic sites with special electronic and topology characteristicsrepresented numerically as the sub-matrix <strong>of</strong> activity, ECSA. An important feature <strong>of</strong> the latter is the set <strong>of</strong> tolerancesin the values <strong>of</strong> the matrix elements which control the quantitative value <strong>of</strong> activity. It was shown that by varying thetolerances one can obtain different toxicophores for different levels <strong>of</strong> activity. A distinguished feature <strong>of</strong> this approachis that it does not employ arbitrary descriptors and statistics at the level <strong>of</strong> toxicophore identification, thus making thelatter void <strong>of</strong> artifacts and chance correlations and fully reliable (at the level <strong>of</strong> reliability <strong>of</strong> the experimental data inthe training set). This led us to suggest a bimolecular mechanism <strong>of</strong> activity for allyl chloride. The toxicophore for 17most active compounds yields a good correlation (R 2 = 0.94) with the experimental activities using only three electronicstructure parameters.References[1] Guner O.F. Ed. Pharmacophore Perception, Development, and Use in Drug Design, International UniversityLine: La Jolla, 2000.[2] Kubinyi, H.; Folkers, G.; Martin, Y. C. 3D QSAR in Drug Design. Volume 3, Recent Advances; Kluwer AcademicPublishers: New York, 2002.[3] Marshall G.R. In: Wolff M.E., Ed. Burger’s medicinal <strong>chemistry</strong> and drug discovery: principles and practice. 5thed. Vol. 1. New York: John Wiley, 1995, 573-659.[4] O. Ivanciuc, Internet Electron. J. Mol. Design, 2, 195–208 (2003).[5] Zhong–Sheng Yi, Shu–Shen Liu, Internet Electron. J. Mol. Design, 4, 835–849 (2005).[6] Verhaar, H.J.M.. Leeuwen, C.J, Hemiens. J.L.M., Chemosphere, 25, 471 -491(1992).[7] I. B. Bersuker, J. Comp.-Aid. Mol. Des., submitted for publication.[8] I. B. Bersuker. Current Pharmaceutical Design., 9, 1575-1606 (2003).[9] Bersuker I. B., Dimoglo A. S., In Reviews in Computational Chemistry; Lipkowitz K.B., Boyd D.B. Eds.; VCH:New York, 1991; vol.2, pp.423-60.[10] Bersuker, I. B.; Bahceci, S.; Boggs, J. E.; Pearlman, R. S. , J. Computer-aided Mol. Design 13, 419–434(1999).[11] Bersuker, I. B.; Bahceci, S.; Boggs, J. E., J. Chem. Inf. Comput. Sci., 40 (2000)1363–1376.[12] Rosines, E.; Bersuker, I. B.; Boggs, J. E., Quan. Struct.-Act. Relat. 2001, 20, 327–334.[13] A. H. Makkouk, I. B. Bersuker and J. E. Boggs, Int. J. Pharm. Med., 18, 81-89 (2004).[14] A.V. Marenich, Pei-Han Yong, I. B. Bersuker and J. E. Boggs, J. Chem. Inf. Mod., submitted.[15] Katritzky, A.R., Tatham, D.B. and Maran U., J. Chem. Inf. Comput. Sci.,41, 1162-1176 (2001).[16] Dearden. J.C. and Raevsky, O.A., SAR and QSAR in Environm. Research, 15, 433-448 (2004).[17] Halgren T. A., J. Comp. Chem. 1996, 17, 490–519.[18] Chambers, C. C.; Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. 1996, 100, 16385–16398.[19] Spartan’02; Wavefunction, Inc.: Irvin, CA. Except for molecular mechanics and semi-empirical models, thecalculation methods used in Spartan’02 have been documented in: Kong, J.; White, C. A.; Krylov, A. I.; Sherrill,D.; Adamson, R. D.; Furlani, T. R.; Lee, M. S.; Lee, A. M.; Gwaltney, S. R.; Adams, T. R.; Ochsenfeld, C.;Gilbert, A. T. B.; Kedziora, G. S.; Rassolov, V. A.; Maurice, D. R.; Nair, N.; Shao, Y.; Besley, N. A.; Maslen, P.E.; Dombroski, J. P.; Daschel, H.; Zhang, W.; Korambath, P. P.; Baker, H.; Byrd, E. F. C.; Voorhis, T. V.; Oumi,103
N.Gorinchoy et al./Chem.J.Mold. 2008, 3 (1), 94-104M.; Hirata, S.; Hsu, C.-P.; Ishikawa, N.; Florian, J.; Warshel, A.; Johnson, B. G.; Gill, P. M. W.; Head-Gordon,M.; Pople, J. A. Q-Chem 2.0: A High-Performance Ab Initio Electronic Structure Program Package. J. Comput.Chem. 2000, 21, 1532–1548.[20] Stewart, J. J. P. , J. Comp. Chem. 1989, 10, 209–220.[21] Basch, H.; Viste, A.; Gray, H. B., Theoret. chim. Acta (Berl.) 1965, 3, 458–464.[22] Bondi, A., J. Phys. Chem. 1964, 68, 441–451).[23] Slater, J. C., J. Chem. Phys. 1964, 41, 3199–3204).[24] Bersuker I.B., Dimoglo A.S., Gorbachov M.Yu., Vlad P.F., Pesaro M. New J. Chem., 15, 307-20 (1991).[25] Metzler, D. E. Bio<strong>chemistry</strong>: The Chemical Reactions <strong>of</strong> Living Cells; Academic Press: New York,1977.104
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