Computational Investigations on Reversal Effect of Acetogenins on Multidrug Resistance Mediated by ABCB1

Abstract

Multi drug resistance (MDR) in tumour is due to over expression of ATP Binding cassette (ABC) transporters such as P-glycoprotein. The combination of non toxic and potent ABC inhibitors along with conventional anticancer drugs is sought for reversing MDR. Several phyto chemicals have been used towards this. Annonaceous acetogenins (AGEs) play a key role towards many varieties of cancer, by strongly inhibiting the NADH oxidase of the plasma membranes of cancer cells. Therefore, current study involves an in silico investigation on a group of AGEs from Annona muricata against ABCB1, using Schrodinger Maestro v11.4 modeling package. Few well characterized AGEs were screened for their ADME properties by Qik Prop module. The selected compounds were then docked with ATP binding sites (Extra precision (XP)) and drug binding site of human P-glycoprotein (PDB ID: 6C0V). The ligand binding affinities were calculated by Prime–MM/GBSA module. Annonacin A and Annonahexocin showed a good docking score with a high MM/GBSA dG binding in both the ATP binding sites than the first generation inhibitors. On the other hand no interactions were observed in the drug binding region. Molecular Dynamic (MD) simulation studies were done to evaluate the stability of the complexes using DESMOND for the generated models. The most significant residues essential for binding interaction were obtained. The results indicate that Annonacin A and Annonahexocin would bind to ATP binding sites stably and not with the drug binding region. Therefore it might only compete with the ATP for binding in the ATP binding region and decrease the total energy required for P-gp rotation. Hence pumping of chemo drugs out of the cells by P-Glycoprotein/ABCB1/MDR1 will be decreased. The Present in silico study helped to identify a potential, natural P-Glycoprotein/ MDR reversal agent. Further experimental studies like drug accumulation assay, ATPase activity are required to validate the same.

Keywords: Multidrug resistance, Acetogenins, ABCB1, Molecular docking, ATP binding Site, Drug binding site, Molecular dynamic simulation