Insight into structural features of phenyltetrazole derivatives as ABCG2 inhibitors for the treatment of multidrug resistance in cancer

ABSTRACT

ABCG2 is the principal ABC transporter involved in the multidrug resistance of breast cancer. Looking at the current demand in the development of ABCG2 inhibitors for the treatment of multidrug-resistant cancer, we have explored structural requirements of phenyltetrazole derivatives for ABCG2 inhibition by combining classical QSAR, Bayesian classification modelling and molecular docking studies. For classical QSAR, structural descriptors were calculated from the free software tool PaDEL-descriptor. Stepwise multiple linear regression (SMLR) was used for model generation. A statistically significant model was generated and validated with different parameters (For training set: r = 0.825; Q² = 0.570 and for test set: r = 0.894, r²_pred = 0.783). The predicted model was found to satisfy the Golbraikh and Trospha criteria for model acceptability. Bayesian classification modelling was also performed (ROC scores were 0.722 and 0.767 for the training and test sets, respectively). Finally, the binding interactions of phenyltetrazole type inhibitor with the ABCG2 receptor were mapped with the help of molecular docking study. The result of the docking analysis is aligned with the classical QSAR and Bayesian classification studies. The combined modelling study will guide the medicinal chemists to act faster in the drug discovery of ABCG2 inhibitors for the management of resistant breast cancer.

KEYWORDS:

• ABCG2
• phenyltetrazole
• PaDEL-descriptor
• classical QSAR
• Bayesian modelling
• molecular docking

Acknowledgments

BB and ATKB are grateful to the All India Council for Technical Education (AICTE), New Delhi for awarding fellowship. SAA sincerely acknowledges Council of Scientific & Industrial Research (CSIR), New Delhi for awarding the Senior Research Fellowship [FILE NO.: 09/096(0967)/2019-EMR-I, Dated: 01-04-2019]. TJ is thankful for the financial support from UPE Phase II and RUSA 2.0 programmes of University Grants Commission (UGC), New Delhi to Jadavpur University, Kolkata, India. We also thank the support from Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India and Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India for providing the research facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data from this article can be accessed at: https://doi.org/10.1080/1062936X.2019.1615545.

Additional information

Funding

This work was supported by the Council of Scientific & Industrial Research, New Delhi [FILE NO.: 09/096(0967)/2019-EMR-I, Dated: 01-04-2019].