MUTAGENICITY PREDICTION FOR NITROAROMATIC COMPOUNDS USING QSTR MODELING
Keywords:
Nitroaromatic, Mutagenicity, Molecular electrostatic profile (MESP), lowest unoccupied molecular orbital (LUMO), Quantitative Structure Toxicity Relationship (QSTR)Abstract
Objective: Nitroaromatic compounds are important industrial chemicals widely used in the synthesis of many diverse products including drugs, dyes, polymers, pesticides and explosives. However, the mutagenicity associated with nitroaromatic compounds is a toxicological feature which poses great concern. On the other hand, there are successful examples of non-mutagenic nitroaromatic molecules; indicating that safer nitroaromatic compounds can be developed. In this light the aim of the present work was to predict the mutagenicity of nitroaromatic compounds using an atom based QSTR model.
Methods: An atom based QSTR model was developed using PHASE. In addition, molecules were studied by complete geometry optimization using DFT at B3LYP/3-21G* level of theory.
Results: An atom based QSTR model was generated for prediction of mutagenicity of the compounds.
Conclusion: The visualization of different properties highlighted key inferences. These include the likelihood of mutagenicity for the molecules with more fused planar hydrophobic rings having hydrogen bond acceptor and electron donating substitutions. Also, all highly mutagenic compounds have two or more negative potential regions. Specific electronic properties such as HOMO and LUMO indicate that most of the mutagenic molecules are very reactive in nature. The results of this study would be useful as a predictive tool to screen out mutagenic nitroarenes and design safer non-mutagenic nitro compounds.
Downloads
References
Debnath AK, Lopez de Compadre RL, DebnathG, Shusterman AJ, Hansch C. Structure-activity relationship of mutagenic aromatic and heteroaromatic nitro compounds. Correlation with molecular orbital energies and hydrophobicity. J Med Chem 1991;34:786-97.
Boelsterli UA, Ho HK, Zhou S, Leow KY. Bioactivation and hepatotoxicity of nitroaromatic drugs. J Curr Drug Metab 2006;7:715-27.
Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, Sasaki H et al. OPC-67683, a nitro-dihydroimidazooxazole derivative with promising action against tuberculosis in vitro and in mice. J PLoS Med 2006;3:2131-44.
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. J Nature 2000;405:962-6.
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N et al. Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. J Antimicrob Agents Chemother 2005;49:2289-93.
Purohit V, Basu A K. Mutagenicity of nitroaromatic compounds. J Chem Res Toxicol 2000;13:673-92.
Sabbioni G. Hemoglobin binding of nitroarenes and quantitative structure activity relationships. J Chem Res Toxicol 1994;7:267-74.
Mc Cann J, Choi E, Yamasaki E, Ames BN. Detection of carcinogens as mutagens in the Salmonella/microsome test:assay of 300 chemicals. L Proc Natl Acad Sci USA 1975;72:5135-9.
Mc Cann J, Spingarn NE, Kobori J, Ames BN. Detection of carcinogens as mutagens:bacterial tester strains with R factor plasmids. J Proc Natl Acad Sci USA 1975;72:979-83.
Zeiger E. Carcinogenicity of mutagens:predictive capability of the Salmonella mutagenesis assay for rodent carcinogenicity. J Cancer Res 1987;47:1287-96.
Benigni R, Bossa C. Mechanisms of Chemical Carcinogenicity and Mutagenicity:A Review with Implications for Predictive Toxicology. J Chem Rev 2011;111:2507-36.
Isayev O, Rasulev B, Gorb L, Leszczynski J. Structure-toxicity relationships of nitroaromatic compounds. Mol Divers 2006;10:233-45.
Basak SC, Mills DR, Balaban AT, Gute BD. Prediction of mutagenicity of aromatic and heteroaromatic amines from Structure:A hierarchical QSAR approach. J ChemInf Comput Sci 2001;41:671-8.
Benigni R, Giuliani A, Franke R, Gruska A. Quantitative structure-activity relationships of mutagenic and carcinogenic aromatic amines. J Chem Rev 2000;100:3697-714.
Benigni R, Zito R. Designing safer drugs:(Q)SAR-based identification of mutagens and carcinogens. J Curr Top Med Chem 2003;3:1289-300.
Gramatica P, Consonni V, Pavan M. Prediction of aromatic amines mutagenicity from theoretical molecular descriptors. J SAR QSAR Environ Res 2003;14:237-50.
Richard AM. International Commission for Protection Against Environmental Mutagens and Carcinogens. Application of SAR methods to non-congeneric data bases associated with carcinogenicity and mutagenicity: issues and approaches. J Mutat Res 1994;305:73-97.
Ashby J, Tennant RW. Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. J Mutat Res 1988;204:17-115.
Hoel DG, Haseman JK, Hogan MD, Huff J, McConnell EE. The impact of toxicity on carcinogenicity studies: implications for risk assessment. J Carcinogenesis 1988;9:2045-52.
Mortelmans K, Zeiger E. The Ames Salmonella/microsome mutagenicity assay. J Mutat Res 2000;455:29-60.
Shelby MD. The genetic toxicity of human carcinogens and its implications. J Mutat Res 1988;204:3-15.
Benigni R. Structure-activity relationship studies of chemical mutagens and carcinogens:mechanistic investigations and prediction approaches. J Chem Rev 2005;105:1767-800.
Maynard AT, Pedersen LG, Posner HS, McKinney JD. An Ab initio study of the relationship between nitroarene mutagenicity and electron affinity. J Mol Pharmacol 1986;29:629-36.
Hu J, Wang W, Zhu Z, Chang H, Pan F, Lin B. Quantitative Structure−Activity Relationship Model for Prediction of Genotoxic Potential for Quinolone Antibacterials. J Environ Sci Technol 2007;41:4806-12.
Smith C. QSAR treatment of multiple toxicities:the mutagenicity and cytotoxicity of quinolines. J Mutat Res 1997;379:167-75.
Tang Y, Chen K, Jiang H, Ji R. QSAR/QSTR of fluoroquinolones:an example of simultaneous analysis of multiple biological activities using neural network method. J Eur Jrnl Med Chem 1998;33:647-58.
Nair PC, Sobhia ME. Comparative QSTR studies for predicting mutagenicity of nitro compounds. J Mol Graph Model 2008;26:916-34.
Bhat KL, Hayik S, Sztandera L, Bock CW. Mutagenicity of Aromatic and Heteroaromatic Amines and Related Compounds:A QSAR Investigation. J QSAR and Comb Sci 2005;24:831-43.
Hatch FT, Colvin ME. Quantitative structure–activity (QSAR) relationships of mutagenic aromatic and heterocyclic amines. J Mutat Res 1997;376:87-96.
Tchounwou PB, Wilson B, Ishaque A, Ransome R, Huang M-J, Leszczynski J. Toxicity Assessment of Atrazine and Related Triazine Compounds in the Microtox Assay, and Computational Modeling for Their Structure-Activity Relationship. Int J Mol Sci 2000;1:63-74.
Bruce E, Autenrieth R, Burghardt R, Donnelly KC, McDonald T. Using Quantitative Structure-Activity Relationships (QSAR) to Predict Toxic Endpoints for Polycyclic Aromatic Hydrocarbons (PAH). J Toxicol Environ Health A 2008;71:1073-84.
Papa E, Pilutti P, Gramatica P. Prediction of PAH mutagenicity in human cells by QSAR classification. J SAR and QSAR Environ Res 2008;19:115-27.
Schmidt TJ, Heilmann J. Quantitative Structure-Cytotoxicity Relationships of Sesquiterpene Lactones derived from partial charge (Q)-based fractional Accessible Surface Area Descriptors (Q_frASAs). J Quant Struct Act Relat 2002;21:276-87.
Scotti MT, Fernandes MB, Ferreira MJP, Emerenciano VP. Quantitative structure–activity relationship of sesquiterpene lactones with cytotoxic activity. J Bioorg Med Chem 2007;15:2927-34.
Goldring JM, Ball LM, Sangaiah R, Gold A. Mutagenic activity of nitro-substituted cyclopenta-fused polycyclic aromatic hydrocarbons towards Salmonella typhimurium. J Mutat Res 1987;187:67-77.
Rosenkranz HS, Mermelstein R. Mutagenicity and genotoxicity of nitroarenes. All nitro-containing chemicals were not created equal. J Mutat Res 1983;114:217-67.
Zielinska B, Arey J, Harger WP, Lee RW. Mutagenic activities of selected nitrofluoranthene derivatives in Salmonella typhimurium strains TA98, TA98NR and TA98/1,8-DNP6. J Mutat Res 1988;206:131-40.
Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA. PHASE: A new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening:1. Methodology and preliminary results. J Comput Aided Mol Des 2006;20:647-71.
Becke AD. Density-functional thermochemistry III. The role of exact exchange. J Chem Phys 1993;98:5648-52.
Becke AD. A new mixing of Hartree–Fock and local density-functional theories. J Chem Phys 1993b;98:1372-77.
Lee C, Yang W, Parr RG. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. J Phys Rev B Condens Matter 1988;37:785-9.
Binkley JS, Pople JA, Hehre WJ. Self-consistent molecular orbital methods. 21. Small split-valence basis sets for first-row elements. J Am Chem Soc 1980;102:939-47.
Gordon MS, Binkley JS, Pople JA, Pietro WJ, Hehre WJ. Self-consistent molecular-orbital methods. 22. Small split-valence basis sets for second-row elements. J Am Chem Soc 1982;104:2797-803.
Pietro WJ, Francl MM, Hehre WJ, DeFrees DJ, Pople JA, Binkley JS. Self-consistent molecular orbital methods. 24. Supplemented small split-valence basis sets for second-row elements. J Am Chem Soc 1982;104:5039-48.
Glende C, Klein M, Schmitt H, Erdinger L, Boche G. Transformation of mutagenic aromatic amines into non-mutagenic species by alkyl substituents. Part II: Alkylation far away from the amino function. J Mutat Res 2002;515:15-38.
Klein M, Voigtmann U, Haack T, Erdinger L, Boche G. From mutagenic to non-mutagenic nitroarenes: Affect of bulky alkyl substituents on the mutagenic activity of 4-nitrobiphenyl in Salmonella typhimurium. Part I. Substituents ortho to the nitro group and in 2'-position. J Mutat Res 2000;467:55-68.
Vance WA, Levin DE. Structural features of nitroaromatics that determine mutagenic activity in Salmonella typhimurium. J Environ Mutagen 1984;6:797-811.