Accessing lipophilicity of drugs with biomimetic models: A comparative study using liposomes and micelles

Loureiro, Daniela R. P.; Soares, José X.; Lopes, Daniela; Macedo, Tiago; Yordanova, Denitsa; Jakobtorweihen, Sven; Nunes, Cláudia; Reis, Salette; Pinto, Madalena; Afonso, Carlos

doi:10.1016/j.ejps.2018.01.029

Cited by 25 publications

(16 citation statements)

References 76 publications

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“…Densities are relative to the phosphorous densities that were set to 1 at the maxima based on the POPC and DOPC lipid distributions for the POPC/chol and PAMPA systems, respectively. The four M-B regions, which are delineated by vertical lines at Z =[6,13,20,27] and correspond to the distance (Å) from the center of the bilayer Z = 0, are noted at the top of each region.…”

mentioning

confidence: 99%

Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation

Lind

Pandey

Pastor

et al. 2021

J. Chem. Theory Comput.

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Small molecules such as metabolites and drugs must pass through the membrane of the cell, a barrier primarily comprising phospholipid bilayers and embedded proteins. To better understand the process of passive diffusion, knowledge of the ability of various functional groups to partition across bilayers and the associated energetics would be of utility. In the present study, the site identification by ligand competitive saturation (SILCS) methodology has been applied to sample the distributions of a diverse set of chemical solutes representing the functional groups of small molecules across phospholipid bilayers composed of 0.9:0.1 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/ cholesterol and a mixture of 0.52:0.18:0.3 1,2-dioleoyl-sn-glycero-3phospho-L-serine/1,2-dioleoyl-sn-glycero-3-phosphocholine/cholesterol used in parallel artificial membrane permeability assay experiments. A combination of oscillating chemical potential grand canonical Monte Carlo and molecular dynamics in the SILCS simulations was applied to achieve solute sampling through the bilayers and surrounding aqueous environment from which the distribution of solutes and the functional groups they represent were obtained. Results show differential distribution of aliphatic versus aromatic groups with the former having increased sampling in the center of the bilayers versus in the region of the glycerol linker for the latter. Variations in the distribution of different polar groups are evident, with large differences between negative acetate and positive methylammonium with accumulation of the polar-neutral and acetate solutes above the bilayer head groups. Conversion of the distributions to absolute free energies allows for a detailed understanding of energetics of functional groups in different regions of the bilayers and for calculation of absolute free-energy profiles of multifunctional drug-like molecules across the bilayers from which partition coefficients and resistance factors suitable for insertion into the homogenous solubility−diffusion equation for calculation of permeability were obtained. Comparisons of the calculated bilayer/solution partition coefficients with 1-octanol/water experimental data for both drug-like molecules and the solutes show overall good agreement, validating the calculated distributions and associated absolute free-energy profiles.

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mentioning

confidence: 99%

Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation

Lind

Pandey

Pastor

et al. 2021

J. Chem. Theory Comput.

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“…It states that molecules with >500 Da molecular weight, >5 hydrogen-bond donors, >5 log P, and >10 hydrogen bond acceptors have poor absorption. Log P (partition coefficient between octanol and water) indicates the lipophilicity of the drug candidate which is a major determinant of the drug-likeness and a value of log P > 0.8 is required to guarantee sufficient membrane permeability and renal clearance [ 95 , 96 ]. An increase in lipophilicity, as observed in case of vinblastine and vincristine, might increase the pharmacodynamic potency, mostly due to the involvement of entropically favored exchanges between the hydrophobic functionalities of the drug and the recognized receptor [ 97 ].…”

Section: Discussionmentioning

confidence: 99%

In silico to In vivo development of a polyherbal against Haemonchus contortus

Rahal

Sharma

Kumar

et al. 2022

Heliyon

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Haemonchus contortus is a major constraint in the development of small ruminant subsector due to significant production losses incurred by it. The present study explores the antiparasitic potential of three anthelmintic plants ( Butea monosperma, Vitex negundo and Catharanthus roseus (L.) G.Don ) against H . contortus taking albendazole as the standard. In silico molecular docking and pharmacokinetic prediction studies were conducted with known bioactive molecules of these plants (palasonin, vinblastine, vincristine, betulinic acid and ursolic acid) against Glutamate Dehydrogenase (GDH) and tubulin molecules of the parasite. Methanolic extracts of these herbs were fractionated (hexane, ethyl acetate, chloroform and methanol) and used in in vitro larvicidal studies. Based on the in vitro data, two herbal prototypes were developed and clinically tested. All the 5 ligand molecules showed better binding affnity for GDH and tubulin protein as compared with albendazole and shared similar binding site in the core of the GDH hexamer with slight variations. Albendazole approximately stacked against GLY190A residue, showing hydrophobic interactions with PRO157A and a Pi-cation electrostatic interaction with ARG390 along with four hydrogen bonds. Vincristine formed 2 pi-anionic electrostatic bonds with ASP158 of B and C subunits alongwith hydrogen bonding and hydrophobic interaction and an additional pi-anion electrostatic interaction at ASP158A for vinblastine. Albendazole bound to α-tubulin next to colchicine site whereas vinblastine is bound at the nearby laulimalide/peloruside site of the dimer. Betulinic acid showed lateral interaction between the H2–H3 loop of one alpha subunit and H10 of the adjacent alpha subunit of two tubulin dimers. Ursolic acid and palasonin bound at the intradimer N site of microtubulin involving the H1–H7 and H1–H2 zone, respectively. The in vitro studies demonstrated good dose dependent anthelmintic potential. Both the prototypes were quite efficacious in clearing the infection, keeping it to a minimal for more than 5 months, probably, through direct anthelmintic effect through GDH, tubulin depolymerization and uncoupling as well as indirectly through immunomodulation along with antioxidant and anti-inflammatory properties.

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“…However, TM only offered statistical significance between the TM-S and CLL formulations (p < 0.01) for the P parameter. The lipophilicity and the location of the drug in the liposome are considered as significant factors influencing the membrane permeability of these drugs [95]. Comparing both drugs for the same formulation, the influence of the drug concentration on the donor compartment was evident.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effect of Acetazolamide-(2-hydroxy)propyl β-Cyclodextrin in Timolol Liposomes for Decreasing and Prolonging Intraocular Pressure Levels

et al. 2021

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The purpose of this study was to design, for the first time, a co-loaded liposomal formulation (CLL) for treatment of glaucoma including timolol maleate (TM) in the lipid bilayer and acetazolamide (Acz)-(2-hydroxy)propyl β-cyclodextrin (HPβCD) complexes (AczHP) solubilized in the aqueous core of liposomes. Formulations with TM (TM-L) and AczHP (AczHP-L), separately, were also prepared and characterized. A preliminary study comprising the Acz/HPβCD complexes and their interaction with cholesterol (a component of the lipid bilayer) was realized. Then, a screening study on formulation factors affecting the quality of the product was carried out following the design of the experiment methodology. In addition, in vitro release and permeation studies and in vivo lowering intraocular pressure (IOP) studies were performed. The results of the inclusion complexation behavior, characterization, and binding ability of Acz with HPβCD showed that HPβCD could enhance the water solubility of Acz despite the weak binding ability of the complex. Ch disturbed the stability and solubility parameters of Acz due to the fact of its competence by CD; thus, Chems (steroid derivative) was selected for further liposome formulation studies. The optimization of the lipid bilayer composition (DDAB, 0.0173 mmol and no double loading) and the extrusion as methods to reduce vesicle size were crucial for improving the physico-chemical properties and encapsulation efficiency of both drugs. In vitro release and permeation studies demonstrated that the CLL formulation showed improvement in in vitro drug release and permeation compared to the liposomal formulations with a single drug (TM-L and AczHP-L) and the standard solutions (TM-S and AczHP-S). CLL showed high efficacy in reducing and prolonging IOP, suggesting that the synergistic effect of TM and Acz on aqueous humor retention and the presence of this cyclodextrin and liposomes as permeation enhancers are responsible for the success of this strategy of co-loading for glaucoma therapy.

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Accessing lipophilicity of drugs with biomimetic models: A comparative study using liposomes and micelles

Cited by 25 publications

References 76 publications

Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation

Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation

In silico to In vivo development of a polyherbal against Haemonchus contortus

Synergistic Effect of Acetazolamide-(2-hydroxy)propyl β-Cyclodextrin in Timolol Liposomes for Decreasing and Prolonging Intraocular Pressure Levels

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