QSAR Modeling for Relative Toxicity Prediction of (3-(2-chloroquinolin-3-yl)oxiran-2-yl)(phenyl)methanone Derivatives
Abstract
2-Chloroquinoline-3-carbaldehyde and its substituted products are extremely versatile intermediates for synthesizing a variety of compounds containing quinoline moiety, which find many pharmaceutical and other applications. Quantitative structure-activity relationship (QSAR) plays an important role in toxicity prediction. The present study deals with acute toxicity predictions LD50 (medianlethal dose) values of (3-(2-chloroquinolin-3-yl)oxiran-2-yl)(phenyl) methanone and its derivatives in rat by oral exposure through QSAR modelling software package T.E.S.T. In the present study the toxicity (LD50) is evaluated using a variety of QSAR methodologies, such as hierarchical clustering, the Food and Drug Administration (FDA) MDL, nearest neighbor and a consensus model. For compounds No. 1 to 4, 7, 10 and 11 hierarchical clustering method does not provide the LD50 values; however, other methods have successfully provided the toxicity estimation for the same. The said software helps to predict the exact LD50 values when compared to experimental data reported in the range (>2000 to >5000 mg/kg). This is a preliminary observation from screening of LD50 values using the said software package. Further study may be relevant using other software to compare the predicted data.
Keywords:
QSAR analysis, Chloroquinoline, Rat, T.E.S.T., Toxicity, median lethal dose
References
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2.Preveena N, Nagendrappa Gopalpur, Suresha Kumara TH, Tiwari Amit Kumar, Chaithanya MS, Nagananda GS, Sujan Ganapathy PS, Tayur N Row Guru, Hosamani Amar A, Chethana PR. Synthesis of (3-(2-Chloroquinolin-3-yl)oxiran-2-yl)(phenyl)methanone derivatives and in vitro and in silico study of their various biological activities. International Journal of Pharmaceutical Science Invention. 2015; 4:6: 53-76.
3.Choplin F. Comprehensive medicinal chemistry. Elsevier Pergamon, Oxford, 2005; 4: 33-57.
4.Valentina P, Lango K and Engels M. Rationalization of physico chemical characters of 2-Phenyl-3-hydroxy-4(1H)-quinolinone-7-carboxylic acid analogs as topoisomerase inhibitors: A QSAR approach. Indian J. Pharm. Educ. Res. 2009; 43:3: 284-289.
5.T. E. S. T. Software Version 4.1 [A Program to Estimate Toxicity from Molecular Structure, developed for United States Environmental Protection Agency, Cincinatti, OH, USA]
6.Yap CW, Xue Y, Li ZR and Chen YZ. Application of support vector machines to in silico prediction of cytochrome P450 enzyme substrates and inhibitors. Curr. Topics Med. Chem. 2006; 6:15: 1593-1607.
7.Guido RV, Oliva G and Andricopulo AD. Virtual screening and its integration with modern drug design technologies. Curr. Med. Chem. 2008; 15:1: 37-46.
8.Schwaighofer A, Schroeter T, Mika S and Blanchard G. How wrong can we get? A review of machine learning approaches and error bars. Comb. Chem. High Throughput Screen. 2009; 12:5: 453-468.
9.Valerio LG Jr. In silico toxicology for the pharmaceutical sciences. Toxicol. Appl. Pharmacol. 2009; 241: 356-370.
10.Kovalishyn V, Kopernyk I, Chumachenko S, Shablykin O, Kondratyuk K, Pil’o S, Prokopenko V, Brovarets V and Metelytsia L. QSAR studies, design, synthesis and antimicrobial evaluation of azole derivatives. Comput. Biol. Bioinfor. 2014; 2:2: 25-32.
11.Worth AP, Bassan A, DeBruijn J, Gallegos Saliner A, Netzeva T, Patlewicz G, Pavan M, Tsakovska I and Eisenreich S. The role of the European Chemicals Bureau in promoting the regulatory use of (Q)SAR methods. SAR and QSAR Env. Res. 2007;18:1-2: 111-125.
12.Lilienblum W, Dekant W, Foth H, Gebel T, Hengstler J, Kahl R, Kramer PJ, Schweinfurth H and Wollin KM. Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch. Toxicol., 2008; 82:4: 211-236.
13.TOPKAT Software User Guide Version 6.2 [A Program developed by Accelrys: San Diego, CA, USA]
14.Dragon Software User Guide 7.0 [A software for the calculation of 4885 molecular descriptors, developed by TALETE srl, Milano, Italy]
15.ADMET Software User Guide, Version 5.5 [A software for Simulation developed by Simulation Plus Inc, SP: Lancaster, CA, USA]
16.Molecular Design Suit (MDS) TM 3.5 [A software developed by V-life Technologies, India]
17.Pallas 3.1.1.2 [An ADME Tox software developed by Computer Drug International Inc, U.S.A.]
18.Yap CW. PaDEL-Descriptor: An open source software to calculate molecular descriptors and fingerprints. J. Comp. Chem. 2011; 32:7: 1466-1474.
19.Martin TM, Harten P, Venkatapathy R, Das, S and Young DM. A hierarchical clustering methodology for the estimation of toxicity. Toxicol. Mech. Methods, 2008; 18:251-266.
20.Zhu H, Martin TM, Ye L, Sedykh A, Young DM and Tropsha A, Quantitative structure-activity relationship modeling of rat acute toxicity by oral exposure. Chem. Res. Toxicol. 2009; 22: 1913-1921.
21.Romesburg HC. Cluster Analysis for Researchers LULU Press, USA (1984).
22.Ruiz P, Begluitti G, Tincher T, Wheeler J and Mumtaz M. Prediction of acute mammalian toxicity using QSAR methods: A case study of sulfur mustard and its breakdown products. Molecules, 2012; 17: 8982-9001.
23.Contrera JF, Matthews EJ and Daniel Benz R. Predicting the carcinogenic potential of pharmaceuticals in rodents using molecular structural similarity and E-state indices. Regul. Toxicol. Pharmacol. 2003; 38: 243-259.
24.Tetko IV, Sushko I, Pandey AK, Zhu H, Tropsha A, Papa E, Oberg T, Todeschini R, Fourches D and Varnek A. Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: Focusing on applicability domain and over fitting by variable selection. J. Chem. Inf. Model., 2008; 48:1733-1746.
25.Gramatica P and Pilutti P. Evaluation of different statistical approaches for the validation of quantitative structure-activity relationships. Ispra, Italy, The European Commission - Joint Research Centre, Institute for Health and Consumer Protection – ECVAM (2004).
26.Golbraikh A and ropsha A. Beware of q2!. J. Mol. Graph. Model. 2002; 20: 269-276.
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How to Cite
Tiwari, A. K., P. Narasimhamurthy, G. Nagendrappa, and A. Thakur. “QSAR Modeling for Relative Toxicity Prediction of (3-(2-Chloroquinolin-3-yl)oxiran-2-yl)(phenyl)methanone Derivatives”. Current Research in Pharmaceutical Sciences, Vol. 7, no. 1, May 2017, pp. 16-24, doi:10.24092/CRPS.2017.070103.
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