Designing of new tetrahydro-β-carboline-based ABCG2 inhibitors using 3D-QSAR, molecular docking, and DFT tools

Abstract

Human ATP-binding cassette superfamily G member 2 (ABCG2) protein is a member of the ABC transporter family, which is responsible for multidrug resistance (MDR) in cancerous cells. MDR reduces the effectiveness of chemotherapy in breast cancer, which is one of the leading causes of death in women globally. MDR in cancer cells is one of the immediate signs of progression of resistance; thus, various anticancer drugs can be designed. To reduce MDR, we utilized the tetrahydro-β-carboline (THβC) compound library. We accomplished a three-dimensional quantitative structure-activity relationship (3D-QSAR), scaffold hopping to design a new library of compounds of THβC, and further molecular docking, induced-fit docking (IFD), molecular mechanics energies combined with generalized born and surface area continuum solvation (MM-GBSA), drug-like features, ADMET properties, and density functional theory (DFT) studies were performed. From these studies, the best 3D-QSAR model (r² = 0.99, q² = 0.92) was found, and the necessity of electrostatic, steric, and hydrophobic field effects were determined that could modulate bioactivity. Moreover, based on electrostatic, steric, and hydrophobic field notations, new THβC derivatives (3409) were designed. These findings might provide new insight for researchers to perform in vitro and in vivo studies for better antagonists against MDR in treating breast cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Breast cancer
• ABCG2
• 3D-QSAR
• Scaffold hopping
• Molecular docking
• DFT
• MM-GBSA
• IFD
• Activity Atlas model

Acknowledgements

SA is thankful to IFTM University, Jamia Millia Islamia and Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology for providing the working environment and excellent infrastructure to pursue the doctoral research work.

Authors’ contributions

SA contributed to extensive in-silico exercises, 3D-QSAR, molecular docking, MM-GBSA, scaffold hopping and DFT investigations, and original draft write-up in the manuscript. DG contributed major inputs, review, and corrections in the manuscript. TA contributed to reviews, and corrections in the manuscript. AI contributed to the final review, correspondence, and corrections in the manuscript.

Disclosure statement

None of the authors have conflicts and declare no competing interests.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.