Title:Computational Modeling on Binding Interactions of Cyclodextrin s with
the Human Multidrug Resistance P-glycoprotein Toward Efficient Drug-delivery
System Applications
Volume: 23
Issue: 1
Author(s): Michael González-Durruthy*, Riccardo Concu*, Laura F. Osmari Vendrame, Mirkos Ortiz Martins, Ivana Zanella, Juan Manuel Ruso and Maria Natália Dias Soeiro Cordeiro*
Affiliation:
- LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
- Soft Matter and Molecular Biophysics Group, Department of Applied Physics, University of Santiago
de Compostela, 15782, Santiago de Compostela, Spain
- LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
- LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
Keywords:
Cyclodextrins, P-glycoprotein, ab initio-DFT, Molecular docking, Nanomedicine, Computational modeling, Binding interactions, Drug selivery system, Multidrug resistance.
Abstract:
Background: 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 observed
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' OHmotifs
with acceptor and donor characteristics, which might theoretically cause local perturbations in the
TMD/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).
Conclusion: Finally, these theoretical results open new horizons for evaluating new nanotherapeutic
drugs with potential pharmacological relevance for efficient drug-delivery applications and precision
nanomedicine.
