Computational binding affinity and molecular dynamic characterization of annonaceous acetogenins at nucleotide binding domain (NBD) of multi-drug resistance ATP-binding cassette sub-family B member 1 (ABCB1)

Abstract

Multi drug resistance (MDR) in tumor might be caused leading to the overexpression of transporters, such as ATP-binding cassette sub-family B member 1 (ABCB1). A combination of non-toxic and potent ABC inhibitors along with conventional anti-cancer drugs is needed to reverse MDR in tumors. A variety of phytochemicals have been previously shown to reverse MDR. Annonaceous acetogenins (AAs) with C₃₅/C₃₇ long-chain fatty acids were reported for their anti-tumor activity, however, their effect on reversing MDR is not yet investigated. We aimed to investigate some selective AAs against the B1 subtype of ABC transporter using computational studies. Various modules of Maestro software were utilized for our in-silico analysis. Few well-characterized AAs were screened for their drug-likeness properties and tested for binding affinity at ATP and drug binding sites of ABCB1 through molecular docking. The stability of the ligand-protein complex (lowest docking score) was then determined by a molecular dynamic (MD) simulation study. Out of 24 AAs, Annonacin A (−8.10 kcal/mol) and Annohexocin (−10.49 kcal/mol) docked with a greater binding affinity at the ATP binding site than the first-generation inhibitor of ABCB1 (Verapamil: −3.86 kcal/mol). MD simulation of Annonacin A: ABCB1 complex for 100 ns also indicated that Annonacin A would stably bind to the ATP binding site. We report that Annonacin A binds at a greater affinity with ABCB1 and might act as a potential drug lead to reverse MDR in tumor cells.

Communicated by Ramaswamy H. Sarma

Keywords:

• Multidrug resistance
• acetogenins
• ABCB1
• molecular docking
• molecular dynamic simulation

Acknowledgments

We thank the management of PSG College of technology and PSG College of Pharmacy, Coimbatore for their support during the course of study. The computational study was carried out at molecular modeling lab facility (Schrödinger Suite), PSG College of Pharmacy, Coimbatore.

Disclosure statement

The authors report no conflicts of interest.

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This article does not contain any work pertaining to the involvement of human participants or animal studies.

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No human studies were conducted and hence not applicable.

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Authors Contribution

All authors contributed equally to the design and implementation of the research. Computational studies were performed by Jeevitha Priya Manoharan, Kavinkumar Nirmala Karunakaran, Subramanian Vidyalakshmi and Karthik Dhananjayan. The first draft of the manuscript was written by Jeevitha Priya Manoharan and modified by Karthik Dhananjayan and Subramanian Vidyalakshmi. All the authors proof read and approved the final manuscript.

Additional information

Funding

No funds, grants or other support was received for conducting this research.