Computational Modeling on Binding Interactions of Cyclodextrin s with the Human Multidrug Resistance P-glycoprotein Toward Efficient Drug delivery System Applications

Abstract

Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: α-CD, β-CD, and γ-CD) family with potential pharmacological relevance and the multidrug resistance P-gp protein toward efficient drug-delivery applications.The treatment of neurological disorders and cancer therapy where the multiple drug-resistance phenomenon mediated by the P-gp protein constitutes the fundamental cause of unsuccessful therapies. Objectives: To understand more about the CD docking mechanism and the P-gp. Methods: In order to achieve the main goal, the computational docking process was used. The observe docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the CD-ligands' OH-motifs with acceptor and donor characteristics, which might theoretically cause local perturbations in theTMD/P-gp inter-residues network, influencing ligand extrusion through the blood-brain barrier. P-gp residues were conformationally favored. Despite the structural differences, all the cyclodextrins exhibit very close Gibbs free binding energy values (or affinity) by the P-gp binding site (transmembrane domains - TMDs). Result: The obtained theoretical docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the OH-motifs of the CD-ligands with acceptor and donor properties which theoretically could induce allosteric local-perturbations in the TMDs-inter-residues network of P-gp modulating to the CD-ligand extrusion from the blood-brain-barrier (or cancer cells). Finally, these theoretical results open new horizons for evaluating new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine