The antimitotic agent paclitaxel continues to play an important role in cancer chemotherapy. However, its inefficacy on certain resistant cells and toxic side effects had led to the search for new drugs with improved biological activity. Here the QSAR models for microtubule stabilizing anticancer agents were performed to correlate their physicochemical properties with biological activity. Single and multiple linear regression models for six cancer cell lines were obtained with R2 ≥ 0.65 and q2pre ≥ 0.6. Molecular mechanics energy and log P of the molecules account for the activity of taxanes towards B16 melanoma and breast cancer cells, respectively. The lowest unoccupied molecular orbitals and the number of nitrogen atoms in the structure account for the biological activity of epothilone derivatives and rest of the drugs towards ovarian cells. The relation between the structural properties of microtubule stabilizing antimitotic compounds and their activities on different cell lines are investigated in this paper. © 2006 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

Mukesh Doble

Department Of Biotechnology

antimitotic agent

antineoplastic agent

BACCATIN III

Docetaxel

EPOTHILONE A

EPOTHILONE B

LAULILAMIDE

Paclitaxel

TACCALONOLIDE A

TACCALONOLIDE E

taxane derivative

unclassified drug

Analysis of variance

animal cell

article

Biological activity

cancer cell culture

controlled study

Correlation coefficient

drug structure

Human

human cell

IC 50

melanoma B16

microtubule

Molecular mechanics

mouse

MULTIPLE LINEAR REGRESSION ANALYSIS

nonhuman

physical chemistry

priority journal

quantitative structure activity relation

three dimensional imaging

IIT Madras is a public technical and research university located in Chennai, Tamil Nadu. Founded in 1959, it is recognised as an Institute of National Importance.

IIT Madras has been ranked as the top engineering institute in India for four years in a row by the National Institutional Ranking Framework of the MHRD

It currently offers undergraduate, postgraduate and research degrees across 16 disciplines in Engineering, Sciences, Humanities and Management. About 596 faculty belonging to science and engineering departments and centres of the Institute are engaged in teaching, research and industrial consultancy.

IIT Madras

QSAR and Combinatorial Science

Eighty semisynthetic taxanes were used to develop a quantitative structure activity relationship (QSAR) and also dock with the microtubule assembly and develop a relationship between binding energy and activity. These two equations could be used to predict activity of new taxanes. The data collected from literature were divided into training (61) and test (19) sets and the former were used to develop the equation. In the QSAR, topological, hydrophobic, and structural descriptors are found to be the major contributors of activity. The statistical parameters r 2 (0.72), r 2 adj (0.69), q 2 (0.65), and F ratio (23.26) were found to be satisfactory and the predictions were with in the 99% confidence interval. The docking studies of taxanes (using training set compounds) using microtubule (PDB: 1JFF) shows that the binding energy is negatively correlated with the antimicrotubule activity (r = -0.66). Hydrogen bond is found to be predominant factor for the binding of the taxanes with the microtubule. The relationship between binding energy and activity (r 2 (0.72), r 2 adj (0.69), q 2 (0.65), and F ratio (23.26)) was able to predict the data in the test set within the 99% confidence limits. In addition, these theoretical studies will give additional inputs to the medicinal chemists to design newer and potent taxane derivatives as antimitotic agents. © Springer Science+Business Media, LLC 2011.

Medicinal Chemistry Research

Computational approaches to enhance activity of taxanes as antimitotic agent

Cytotoxic activity of 47 semi-synthetic Taxoteres against four different cancer cell lines, such as ovarian cancer (A121), human colon adenocarcinoma (HT29), human breast cancer (MCF7) and drug-resistant human breast cancer (MCF7R), was used to develop a quantitative structure-cytotoxicity relationship (QSCR). The data were divided into training (38) and test sets (9), in which the former was used to develop the QSCR and the later was used for the prediction of three of the cell lines namely A121, HT29 and MCF7. In the case of MCF7R, the training set contained 36 compounds and the test set contained nine compounds. The statistical measures such as squared correlation coefficient (r 2=0.73-0.81), adjusted squared correlation coefficient (r 2 adj =0.72-0.80), cross-correlation coefficient (q2 =0.62-0.75) and F-ratio (17.49-27.49) were found to be satisfactory. Other statistical diagnoses such as n/p ratio, fraction of the variance in terms of r2 and quality factor (Q) were also satisfactory. Thermodynamic, lipophilic/hydrophilic, spatial (Jurs descriptors) and topological (Kier and Hall connectivity indices) descriptors contributed to the activity. Functional groups required at R1-R3 positions for enhanced activity are discussed. The developed QSCR models can be used in the design and development of newer semi-synthetic Taxotere derivatives for the cancer therapy. © 2011 Taylor &amp; Francis.

Molecular Simulation

Quantitative structure-cytotoxicity relationships (QSCR) for semi-synthetic Taxoteres against cancer cell lines

Nanotechnology

The binding mode of epothilone A on a,b-tubulin by electron crystallography

Proceedings of the National Academy of Sciences

Microtubule-stabilizing agents based on designed laulimalide analogues

Il Farmaco

3D QSAR studies for the β-tubulin binding site of microtubule-stabilizing anticancer agents (MSAAs)

Angewandte Chemie International Edition

Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues

3-D QSAR studies of microtubule stabilizing antimitotic agents towards six cancer cell lines

Journal	QSAR and Combinatorial Science
ISSN	1611020X
Open Access	No