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

• Type: Article in International Scientific Journal
• Date: 2023

Authors

González-Durruthy, M (Author) Other; Riccardo Concu (Author) FCUP; Natalia N D S Cordeiro (Author) FCUP; Osmari Vendrame, LF (Author) Other; Ortiz Martins, M (Author) Other; Zanella, I (Author) Other; Ruso, JM (Author) Other

Journal

Title: Current Topics in Medicinal Chemistry

Vol. 23

Pages: 62-75

ISSN: 1568-0266

Publisher: Bentham Science

Indexing

ISI Web of Knowledge - 3 Citations

Other information

Authenticus ID: P-00Y-BBE

DOI: 10.2174/1568026622666220303115102

Abstract (EN): <jats:sec> <jats:title>Background:</jats:title> <jats:p>Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: ¿-CD, ß-CD, and ¿-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.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>To understand more about the CD docking mechanism and the P-gp.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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' OH-motifs 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).</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Finally, these theoretical results open new horizons for evaluating new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine.</jats:p> </jats:sec>

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14