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

Abstract

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