RESUMO
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, ß-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.