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Study on reversal of ABCB1 mediated multidrug resistance in Colon cancer by acetogenins: An in - silico approach.
- Source :
-
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2022 Jun; Vol. 40 (9), pp. 4273-4284. Date of Electronic Publication: 2020 Dec 07. - Publication Year :
- 2022
-
Abstract
- 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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 chemistry
Adenosine Triphosphate
Cell Line, Tumor
Humans
Neoplasm Proteins
Acetogenins chemistry
Acetogenins pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Colonic Neoplasms drug therapy
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Subjects
Details
- Language :
- English
- ISSN :
- 1538-0254
- Volume :
- 40
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular structure & dynamics
- Publication Type :
- Academic Journal
- Accession number :
- 33280531
- Full Text :
- https://doi.org/10.1080/07391102.2020.1855249