This work aimed to combine different experiments and multi-scale theoretical approaches to understand the adsorption process of methylene blue in three-dimensional graphene-based materials. For this, experiments were carried out on...

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In this work, one of the most prevalent polypharmacology drug–drug interaction events that occurs between two widely used beta-blocker drugs—i.e., acebutolol and propranolol—with the most abundant blood plasma fibrinogen protein was evaluated. Towards that end, molecular docking and Density Functional Theory (DFT) calculations were used as complementary tools. A fibrinogen crystallographic validation for the three best ranked binding-sites shows 100% of conformationally favored residues with total absence of restricted flexibility. From those three sites, results on both the binding-site druggability and ligand transport analysis-based free energy trajectories pointed out the most preferred biophysical environment site for drug–drug interactions. Furthermore, the total affinity for the stabilization of the drug–drug complexes was mostly influenced by steric energy contributions, based mainly on multiple hydrophobic contacts with critical residues (THR22: P and SER50: Q) in such best-ranked site. Additionally, the DFT calculations revealed that the beta-blocker drug–drug complexes have a spontaneous thermodynamic stabilization following the same affinity order obtained in the docking simulations, without covalent-bond formation between both interacting beta-blockers in the best-ranked site. Lastly, experimental ultrasound density and velocity measurements were performed and allowed us to validate and corroborate the computational obtained results.

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Aims: 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 Background: 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 Objective: Undercover the docking mechanism of the CDs and the P-gp-.Methods: Use of the computational docking methodology to reach the main aim. Results: The observed docking-mechanism of the CDs on the P-gp were 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 local perturbations in the TMD/P-gp inter-residues network modulating to the ligand extrusion from the blood-brain-barrier. Conclusion: These theoretical results open new horizons for the evaluation of new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery for nanomedicine applications. 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). The obtained theoretical docking-mechanism of the CDs on the P-gp were 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 the evaluation of new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine.