Dataset Information

Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

ABSTRACT: Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.

SUBMITTER: Haque A

PROVIDER: S-EPMC8954655 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

Haque Absarul A Baig Ghazanfar Ali GA Alshawli Abdulelah Saleh AS Sait Khalid Hussain Wali KHW Hafeez Bilal Bin BB Tripathi Manish Kumar MK Alghamdi Badrah Saeed BS Mohammed Ali Hani S H HSH Rasool Mahmood M

Life (Basel, Switzerland) 20220307 3

Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the bindi ...[more]

PMID: 35330134

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Project description:BackgroundToll-like receptor 9 (TLR9) recognises unmethylated CpG DNA and activates a signalling cascade, leading to the production of inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-12 via the adaptor protein MyD88. However, the specific sequence and structural requirements of the CpG DNA for the recognition of and binding to TLR9 are unknown. Moreover, the 3D structures of TLR9 and the TLR9-ODN complex have not been determined. In this study, we propose a reliable model of the interaction of the TLR9 ECD with CpG ODN using bioinformatics tools.ResultsThe three-dimensional structures of two TLR9 ECD-CpG ODN complexes were constructed using a homology modelling and docking strategy. Based on the models of these complexes, the TLR9 ECD-CpG ODN interaction patterns were calculated. The results showed that the interface between the human TLR9 and the CpG ODN molecule is geometrically complementary. The computed molecular interactions indicated that LRR11 is the main region of TLR9 that binds to CpG ODN and that five positively charged residues within LRR11 are involved in the binding of the TLR9 ECD to the CpG ODN. Observations in the close-up view of these interactions indicated that these five positively charged residues contribute differently to the binding region within the TLR9 ECD-CpG ODN complex. 337Arg and 338Lys reside in the binding sites of ODN, forming hydrogen bonds and direct contacts with the CpG ODN, whereas 347Lys, 348Arg, and 353His do not directly contact the CpG ODN. These results are in agreement with previously reported experimental data.ConclusionIn this study, we present two structural models for the human and mouse TLR9 ECD in a complex with CpG ODN. Some features predicted by this model are consistent with previously reported experimental data. This complex model may lead to a better understanding of the function of TLR9 and its interaction with CpG ODN and will improve our understanding of TLR9-ligand interaction in general.

Dataset Information

Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

Publications

Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

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