González-Durruthy, MichaelConcu, RiccardoOsmari Vendrame, Laura F.Ortiz Martins, MirkosZanella, IvanaRuso Beiras, Juan ManuelCordeiro, M. Natália D. S.2025-12-052025-12-052023-01-25Michael González-Durruthy, Concu, R., Vendrame, L. F. O., Mirkos, O. M., Zanella, I., Juan, M. R., & Maria Natália Dias, S. C. (2023). Computational modeling on binding interactions of cyclodextrin s with the human multidrug resistance P-glycoprotein toward efficient drug-delivery system applications doi:10.2174/15680266226662203031151021568-0266https://hdl.handle.net/10347/44255Herein, 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 nanomedicineengAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/CyclodextrinsP-glycoproteinab initio-DFTMolecular dockingNanomedicineComputational modelingBinding interactionsDrug selivery systemMultidrug resistancejournal article10.2174/15680266226662203031151021873-4294open access