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.