Quantitative analysis of structure-activity relationships of tetrahydro-2H-isoindole cyclooxygenase-2 inhibitors
- 86 Downloads
Using the GUSAR program, structure-activity relationships on inhibition of cyclooxygenase-2 (COX-2) catalytic activity were quantitatively analyzed for twenty-six derivatives of 4,5,6,7-tetrahydro-2H-isoindole, 2,3-dihydro-1H-pyrrolyzine, and benzothiophene in the concentration range of 0.6–700 nmol/liter IC50 values. Six statistically significant consensus QSAR models for prediction of IC50 values were designed based on MNA- and QNA-descriptors and their combinations. These models demonstrated high accuracy in the prediction of IC50 values for structures of both training and test sets. Structural fragments of the COX-2 inhibitors capable of strengthening or weakening the desired property were determined using the same program. This information can be taken into consideration on molecular design of new COX-2 inhibitors. It was shown that in most cases, the influence of structural fragments on the inhibitory activity of the studied compounds revealed with the GUSAR program coincided with the results of expert evaluation of their effects based on known experimental data, and this can be used for optimization of structures to change the value of their biological activity.
Key wordscyclooxygenase-2 inhibitors GUSAR QSAR models QNA and MNA descriptors analysis of structure-activity relationships
General Unrestricted Structure-Activity Relationships
Multilevel Neighborhoods of Atoms
Quantitative Structure-Activity Relationships
Unable to display preview. Download preview PDF.
- 8.Holtje, H.-D., Sippl, W., Rognan, D., and Folkers, G. (2010) Molecular Modeling: Basic Principles and Applications (Palyulin, V. A., and Radchenko, E. V., eds.) [Russian translation], BINOM, Laboratoriya Znanii, Moscow.Google Scholar
- 9.Ivanov, A. S., Veselovsky, A. V., Dubanov, A. V., Skvortsov, V. S., and Archakov, A. I. (2006) The integral platform “From gene to drug prototype” in silico and in vitro, Ross. Khim. Zh., L, 18–35.Google Scholar
- 10.Khan, M. S., and Khan, Z. H. (2003) Molecular modeling for generation of structural and molecular electronic descriptors for QSAR using quantum mechanical semiempirical and ab initio methods, Genome Informatics, 14, 486–487.Google Scholar
- 11.Filimonov, D. A., and Poroikov, V. V. (2006) Prediction of the biological activity spectrum of organic compounds, Ross. Khim. Zh., L, 66–75.Google Scholar
- 12.Poroikov, V. V., and Filimonov, D. A. (2001) Computeraided prediction of biological activity of chemical compounds as a basis for search and optimization of basic structures of new drugs, in Nitrous Heterocycles and Alkaloids (Kartsev, V. G., and Tolstikov, G. A., eds.) [in Russian], Iridium-Press, Moscow, Vol. 1, pp. 123–129.Google Scholar
- 13.Lagunin, A. A., Gloriozova, T. A., Dmitriev, A. V., Volgina, N. E., and Poroikov, V. V. (2012) Computerized assessment of interactions of pharmaceuticals with P-glycoprotein, Byull. Eksp. Biol. Med., 154, 520–524.Google Scholar
- 17.Masanda, V. H., Mahajana, D. T., Patil, K. N., Dawale, N. E., Hadda, T. B., Alafeefy, A. A., and Chinchkhede, K. D. (2011) General unrestricted structure activity relationships based evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors, Der Pharma Chemica, 3, 517–525.Google Scholar
- 19.Taipov, I. A., Khayrullina, V. R., Gerchikov, A. Ya., Khoma, V. K., Zarudiy, and Begel, Kh. (2012) Virtual screening in the row of effective inhibitors of catalytic activity of leukotriene-A4-hydrolase, Vestnik Bashkir. Univ., 17, 886–891.Google Scholar
- 20.Tarasov, G. P., Khairullina, V. R., Gerchikov, A. Ya., Kirlan, S. A., and Zarudiy, F. S. (2012) Derivatives of 4-amino-N-[2-(diethylamino)ethyl]benzamide as potentially low toxicity substances with a pronounced anti-arrhythmic action, Vestnik Bashkir. Univ., 17, 1242–1246.Google Scholar
- 21.Khayrullina, V. R., Kirlan, S. A., Gerchikov, A. Ya., Zarudiy, F. S., Dimoglo, A. S., and Kantor, E. A. (2010) Modeling structures of anti-inflammatory compounds on considering their toxicity, Bashkir. Khim. Zh., 17, 76–79.Google Scholar
- 22.MarvinSketch (http://www.chemaxon.com/download/marvin-suite).
- 23.Discovery Studio Visualiser (http://accelrys.com/resource-center/downloads/freeware/index.html).
- 24.Portevin, B., Tordjman, C., Pastoureau, P., Bonnet, J., and De Nanteuil, G. (2000) 1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: a new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite, J. Med. Chem., 43, 4582–4593.PubMedCrossRefGoogle Scholar
- 27.Ravdel, A. A., and Ponomareva, A. M. (eds.) (2003) Short Reference Book of Physicochemical Values [in Russian], Ivan Fedorov, St. Petersburg, pp. 212–213.Google Scholar