RESUMEN
Multi-Drug Resistance (MDR) exerted by tumor cells is majorly due to the overexpression of ATP Binding cassette transporters such as ABCB1/P-glycoprotein (P-gp). Annonaceous acetogenins (AGEs) exert anticancer activity by strongly inhibiting NADH oxidase of cancer cells. The present in silico study aims at screening a potent MDR inhibitor among acetogenins from the plant Annona muricata. Twenty-four AGEs were selected and screened for their pharmacokinetic properties. An inward facing conformation of P-gp is required for understanding the interaction of AGEs at the drug binding region and hence the human P-gp protein was modeled. The selected compounds were then docked with the ATP binding site and the drug binding site of modeled human P-gp. Annonacin A.1, Annohexocin.1 and Annomuricin E.1 docked better with high MM/GBSA dG binding in the drug binding region as compared with the conventional drugs. These compounds had a better docking score as compared with control inhibitor drugs at the ATP binding region. The complexes were subjected to MD simulation and Annonacin A was stable throughout the simulation period. Therefore, Annonacin A might act as a competitive inhibitor for the chemo drugs for binding at the drug binding region of P-gp. Hence it is capable of decreasing the efflux of chemo drugs out of the cells by P-Glycoprotein/ABCB1/MDR1. With this computational study, it is concluded that this compound might potentially reverse MDR, and hence can be taken forward for validation studies.Communicated by Ramaswamy H. Sarma.