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

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.

Biomolecular interactions: essential instrumentation methods.

The main goal of this review is to outline the basic principles and applications of the broad range of modern biophysical technical methods used to study the different aspects of protein­ligand interactions by discussing such aspects as newer systems, unusual approaches and highly used techniques.

Thermodynamic and elastic fluctuation analysis of Langmuir mixed monolayers composed by dehydrocholic acid (HDHC) and didodecyldimethylammonium bromide (DDAB).

The physicochemical and elastic properties of Langmuir mixed monolayers composed by dehydrocholic acid (HDHC) and didodecyldimethylammonium bromide (DDAB) were evaluated. The experiments were performed with a constant surface pressure penetration Langmuir balance based on Axisymmetric Drop Shape Analysis (ADSA). The behavior of such amphiphiles in monolayer was clearly non-ideal and would be seriously influenced by the amount of HDHC molecules present. The presence of bile acid type molecules caused the monolayer be more condensed (A(c) diminution) and the intermolecular attractive interactions be stronger (high epsilon(0) values). This fact would be related to H-bond formation between water and carboxilate and carbonile groups in the cholesteric ring and agreed with the existence of laterally structured microdomains at the monolayer (determined by the analysis of the first virial coefficient, b(0)<1, of the state equation). The miscibility of both surfactants in the monolayer, their high bulk hydrophobicity (pi(c)>35 mJ m(-2)) just with the obtained negative values of the free energy of mixing Delta G(mix), and the excess second virial coefficient (b(1))(E) obtained allows us to infer that net attractive interaction existed between HDHC and DDAB molecules at the monolayer and that mixed systems would be able to be used in the formulation of supramolecular assemblies.