Modeling drug-drug interactions of AZD1208 with Vincristine and Daunorubicin on ligand-extrusion binding TMD-domains of multidrug resistance P-glycoprotein (ABCB1)

• DOI: 10.1016/j.tox.2018.10.009
• Publication Date: 2018-10-17T02:34:55Z
• Authors: Maiara Bernardes ...; Patricia Viera de...; Solange Binotto F...; Bruno Rodrigues O...; Bruna Félix da Si...; Daniela Volcan Al...; Luis Fernando Marins; Michael González-...
• Keywords: Daunorubicin; Docking (animal); Ramachandran plot; P-glycoprotein

In the present study, molecular docking mechanism based on pharmacodynamic interactions between ligands AZD1208 and recognized chemotherapy agents (Vincristine Daunorubicin) with human ATP-binding cassette (ABC) transporters (ABCB1) was investigated. For first time, were combined an in silico approaches like ab initio computational simulation Density Functional Theory (DFT) to explain drug-drug interaction of aforementioned transmembrane ligand extrusion binding domains (TMDs) ABCB1. this regard, theoretical characterized by using Gibbs free energy (FEB, kcal/mol) from best ABCB1-ligand complexes. The results pointing that for three complexes are mainly non-covalent hydrophobic hydrogen-bond showing a similar toxicodynamic behavior terms strength very close energies when compared FEB-values ABCB1 specific-inhibitor (Rhodamine B) = -6.0 kcal/mol used as control compare FEB (AZD1208-ABCB1) ∼ (Vincristine-ABCB1) (Daunorubicin-ABCB1) -6.2 average. Ramachandran plot suggests 3D-crystallographic structure transporter can be efficiently-modeled conformationally-favored Psi versus Phi dihedral angles all key TMDs-residues. Though, DFT-simulation corroborate existence (AZD1208/Vincristine) > (AZD1208/Daunorubicin). These pieces evidence have preclinical relevance potential design new drugs understand polypharmacology influence multiple-drugs resistance, contributing higher success prognosis cancer patients.