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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2023

Autores

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

Revista

Título: Current Topics in Medicinal Chemistry

Vol. 23

Páginas: 62-75

ISSN: 1568-0266

Editora: Bentham Science

Indexação

ISI Web of Knowledge - 3 Citações

Scopus - 3 Citações

Outras Informações

ID Authenticus: P-00Y-BBE

DOI: 10.2174/1568026622666220303115102

Abstract (EN): Background Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: alpha-CD, beta-CD, and gamma-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' 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). 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 14