3D-QSAR and docking studies on ursolic acid derivatives for anticancer activity based on bladder cell line T24 targeting NF-kB pathway inhibition

Abstract

Bladder cancer is the common reason for mortality worldwide, and its increasing rate announces as a significant area of research in drug designing. The side effects and toxicity of existing drugs and the consequence of gradual cancer cell resistance against the available therapy make the treatment poor. Globally, there is a continuous high demand to develop new, more potent, and easily affordable drugs against cancer. The current research article illustrates the application of developed three-dimensional quantitative structure-activity relationship (3D-QSAR) based on human bladder cancer cell line T24 in vitro anticancer activity. The derived QSAR model has been used for prediction of natural compounds and analogs with 80% similarity of the most active compound of the dataset. The developed model describes the structure-activity relationship for terpenes and their derivatives at the molecular level. The developed comparative molecular field analysis (CoMFA) model shows a satisfactory cross-validation correlation coefficient (q²) of 0.54 and a regression correlation coefficient (r²) of 0.86. In order to evaluate the compliance with electronic pharmacokinetic parameters, Lipinski’s rule of five filter, absorption, distribution, metabolism, and excretion (ADME) and toxicity of predicted compounds have been calculated. Furthermore, molecular-docking study has been performed to prioritize these predicted compounds based on their docking score and binding pocket similarity through the identified potential anticancer targets. Finally, two compounds T9 and B42 have been identified as the best hit because these two fall within the standard limits of all filters and show a good binding affinity. Conclusively, all satisfactory results strongly suggest that the derived 3D-QSAR model and obtained candidate’s binding structures are reasonable in the prediction of a new antagonist’s activity. The strategy adopted in the present research is expected to be of immense importance and a great support in the identification and optimization of lead in the early and advance drug discovery.

Keywords:

• 3D-QSAR
• CoMFA
• ursolic acid
• terpenoids
• NF-κB
• ADMET
• docking

Acknowledgements

We are thankful to the Director, CSIR-CIMAP, Lucknow India, for rendering essential research facilities and support. We acknowledge the Director, Institute of Engineering and Technology, Lucknow, and Vice Chancellor, Dr. A.P.J. Abdul Kalam Technical University, Uttar Pradesh, Lucknow, for providing required research supporting environment. Author DY acknowledges the Indian Council of Medical Research (ICMR), New Delhi for financial support through Senior Research Fellowship (SRF) (letter no.-5/3/8/10/ITR dated 09-04-2018) at CSIR-CIMAP, Lucknow. The CIMAP communication no. is CIMAP/PUB/2018/27.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

The authors are thankful to the Indian Council of Medical Research (ICMR), New Delhi [vide award letter no. 5/3/8/10/ITR-F/2018-ITR] for financial support at CSIR-CIMAP, Lucknow.

Notes on contributors

Deepika Yadav

DY performed the actual experimentation, recorded data, analyzed results and prepared the draft manuscript.

Bhartendu Nath Mishra

BNM analyzed and interpreted the results and checked the manuscript.

Feroz Khan

FK conceptualized the work, designed the experiment , interpreted the result and edited the final manuscript.