|Year : 2009 | Volume
| Issue : 1 | Page : 77-81
QSAR analysis on β-carboline as antitumor agent
P Valentina, K Ilango, K Yamuna, D Purushothaman, A Samyuktha Rani
Department of Pharmaceutical Chemistry, S.R.M. College of Pharmacy, S.R.M. University, Kattankulathur 603203, Tamil Nadu, India
Department of Pharmaceutical Chemistry, S.R.M. College of Pharmacy, S.R.M. University, Kattankulathur 603203, Tamil Nadu
A quantitative structure activity relationship (QSAR) study on β-Carboline derivatives as an anti-tumor agent was performed with 30 compounds of β-Carboline derivatives on different cancer cell lines from reported work. Molecular modeling studies were performed using ChemBioDraw Ultra 11.0. The sketched structures were subjected to energy minimization and the lowest energy structure was used to calculate the physiochemical properties. The regression analysis was carried out using a computer program called Valstat. The best models were selected from the various statistically significant equations. From the derived QSAR model, it can be concluded that the cytotoxic activity of β-carboline derivatives is strongly influenced by the thermodynamic and electronic nature of the substituents.
Keywords: Anti-tumor agent, β-carboline, QSAR
|How to cite this article:|
Valentina P, Ilango K, Yamuna K, Purushothaman D, Samyuktha Rani A. QSAR analysis on β-carboline as antitumor agent. J Young Pharmacists 2009;1:77-81
|How to cite this URL:|
Valentina P, Ilango K, Yamuna K, Purushothaman D, Samyuktha Rani A. QSAR analysis on β-carboline as antitumor agent. J Young Pharmacists [serial online] 2009 [cited 2014 Mar 8];1:77-81. Available from: http://www.jyoungpharm.in/text.asp?2009/1/1/77/51880
| Introduction|| |
Research on antitumor alkaloids isolated from plants have been actively explored in the last 30 years, in which the anti-tumor effects of the naturally occurring β-c arboline derivative have been noticed recently after an intensive concentration on their high affinity to 5-HT  and benzodiazepines receptors , that cause CNS effect. As far the antitumor activity, harmine is a β-Carboline derivative shown to have strong cytotoxic activity to tumor cell lines in vitro .  It was recently discovered that β-carboline derivatives may function their antitumor activity through multiple mechanisms such as inhibiting topoisomerase - I and II,,,,, β-kinase complex, , and intercalating DNA.  There are several reports on other biological activity of β-carboline derivatives, as well. QSAR is a useful tool for a retinal search of bioactive compounds. It provides a deeper insight into the mechanism of drug receptor interaction. Hence, in the present paper we report a QSAR study on a set of β-carboline derivatives for their in vitro antitumor activity against 6 different cell lines. In short, this study may provide a framework for designing a novel anti-tumor agent.
| Materials and Methods|| |
Data sets of 30 molecules have been taken from the published results.  The cytotoxic activity expressed as IC 50 values have been converted into -log molar concentration ( p IC 50 ) to reduce the stewness of the data set. The structure and cytotoxic activity data ( p IC 50 ) are given in [Table 1].
Molecular structure generation
The structure of the β-carboline derivatives were sketched using ChemBioDraw Ultra 11.0 and it has been saved as a template structure. The molecular mechanics (MM 2) method was applied to search for lower energy conformations for each molecule. The energy minimized molecules were subjected to re-optimization via the Austin model - 1 method until the root mean square gradient attained a value smaller than 0.001k cal/mol using molecular orbital property accompany name (MOPAC). The geometry optimization of the lowest energy structure was carried out using the Eigen vector following (EF) routine.
The thermodynamic, spatial, electronic, and topological parameters shown in [Table 2] were calculated for QSAR analysis. Thermodynamic parameters describe free energy change during drug receptor complex formation. Spatial parameters were quantified for steric features of drug molecules required for its complimentary fit with the receptor. Electronic parameters describe weak non-covalent bonding between drug molecules and the receptor.
In order to select the predominant descriptors affecting the cytotoxic activity, the correlation analysis was performed using the statistical software Valstat.  Multiple regression analysis was used to generate QSAR analysis. The statistical measures used were: n=number of samples in the regression, r=correlation coefficient, and s=standard deviation. The robustness and applicability of the QSAR equation obtained on the structural analogs were further performed using various validation methods, bootstrapping squared correlation coefficients (r 2 bs), and randomized biological data test (chance).
| Results and Discussion|| |
Among the several models, one of the best models was selected from each cell line and the results are summarized in [Table 3]. The best QSAR model has characters of large F, small r and s, low p-value, r 2 and q 2 values close to 1, as well as P <0.001. So the tabulated QSAR shows significant statistical quality. The equation was further validated using the Loo cross validation method to confirm the internal consistency given in [Table 4] and it suggests a good correlation between the physiochemical parameters and the antitumor activity. The bootstrapping r 2 bs value showed that the model is quite robust.
For the cell line BGC823, the thermodynamic parameters, log P, CMA, and EM play a significant role. The negative coefficient of log p indicates that the length of the carbon chain should be optimized and the hydrophobicity should be reduced. The negative contribution of EM indicates that the bulkiness should be reduced. The electronic parameter LUMO contributes negative coefficients for the cell lines Lovo, Hela, and C 6 .The energy LUMO is directly related to the electron affinity and characterize the susceptibility of the molecule towards attack of nucleophile. The energy of LUMO can be decreased by an electron releasing substituent and the lowering of LUMO energy will increase the magnitude of inhibitory activity. When a molecule acts as a lewis base in bond formation, the electrons are supplied from the molecules. A positive contribution of HOMO in the cell line C6 indicates that they are more susceptible to electrophilic attack. The thermodynamic parameters SE and SBE showed positive contribution to the cell lines LOVO and Hela. The geometric descriptor principal moment of inertia (PMI) helps to characterize the shape of the molecules and shows a positive effect on all the cell lines expect BGC823. The descriptor VDW energy is non bonded Van der Waals energy between the molecule and the receptor shows a negative contribution to Be17402 cell line.
| Conclusion|| |
In summary, from the derived QSAR model, it may be concluded that selective cytotoxic activity by the β-carboline derivative is strongly influenced by the thermodynamic and electronic nature of the substituents. Patterns of substitution can be extracted from the developed model, which may be helpful in the development and optimization of cytotoxic inhibitors of this class of compounds.
| Acknowledgements|| |
The authors are grateful to Dr. R. Shivakumar, Pro-Vice Chancellor, S.R.M. University and Dr. K.S. Lakshmi, Dean, College of Pharmacy, S.R.M. University, Kattankulathur for providing the necessary facilities to carry out this research.
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[Table 1], [Table 2], [Table 3], [Table 4]