Thermodynamic study of benzocaine insertion into different lipid bilayers

Cascales, J.J. López; Costa, S. D. Oliveira; Porasso, Rodolfo D.

doi:10.1063/1.3643496

Cited by 24 publications

(18 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides, z-constrained MD offers some advantages with respect to other methods, in that it has been validated, 31,40,59,60 and successfully applied to quite many solute/membrane systems. 31,32,[60][61][62][63] In view of the extension to more complex systems, we are currently testing other approaches, such as meta-dynamics [64][65][66][67][68] and adaptive biasing force. [69][70][71] The inclusion of polarization effects 72,73 would additionally be considered as a major step toward a more realistic description of the molecular interactions.…”

Section: Discussionmentioning

confidence: 99%

From dioxin to dioxin congeners: understanding the differences in hydrophobic aggregation in water and absorption into lipid membranes by means of atomistic simulations

Casalegno

Raos

Sello

2016

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

Translocation of small molecules through a cell membrane barrier is a fundamental step to explain the response of cells to foreign molecules. Investigating the mechanisms through which this complex process takes place is especially important in the study of the adverse effects of toxicants. In this work, we start from the results of a previous simulation study of the mechanism of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) absorption into a model membrane, and extend it to four structural congeners of dioxin. The new molecules have been chosen taking into consideration the structural features that characterize dioxin: aromaticity, planarity, the presence of chlorine and oxygen atoms, and hydrophobicity. Our results for the absorption mechanism confirm our expectations based on the chemical structures, but also reveal some interesting differences in single-molecules and especially in cooperative actions underlying cluster absorption. The analysis of key parameters, such as free energies of transfer and translocation times, supports the idea that dioxin, more than its congeners investigated here, likely accumulates in cell membranes.

show abstract

Section: Discussionmentioning

confidence: 99%

From dioxin to dioxin congeners: understanding the differences in hydrophobic aggregation in water and absorption into lipid membranes by means of atomistic simulations

Casalegno

Raos

Sello

2016

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

show abstract

“… and Cascales et al . studied interactions of two benzocaine molecules with symmetric and asymmetric mixed bilayers containing DPPC (1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine) and DPPS (1,2‐dipalmitoyl‐sn‐glycero‐3‐phospho‐L‐serine) lipids in different leaflets. In both cases, benzocaine decreased the lipid tail order parameters, and, although benzocaine is uncharged, its effect is more pronounced for negatively charged DPPS lipids.…”

Section: Interactions Of Drugs With Bilayersmentioning

confidence: 99%

Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes

2013

View full text Add to dashboard Cite

Several small drugs and medicinal plant extracts, such as the Indian spice extract curcumin, have a wide range of useful pharmacological properties that cannot be ascribed to binding to a single protein target alone. The lipid bilayer membrane is thought to mediate the effects of many such molecules directly via perturbation of the plasma membrane structure and dynamics, or indirectly by modulating transmembrane protein conformational equilibria. Furthermore, for bioavailability, drugs must interact with and eventually permeate the lipid bilayer barrier on the surface of cells. Biophysical studies of the interactions of drugs and plant extracts are therefore of interest. Molecular dynamics simulations, which can access time and length scales that are not simultaneously accessible by other experimental methods, are often used to obtain quantitative molecular and thermodynamic descriptions of these interactions, often with complementary biophysical measurements. This review considers recent molecular dynamics simulations of small drug‐like molecules with membranes, and provides a biophysical description of possible routes of membrane‐mediated pharmacological effects of drugs. The review is not exhaustive, and we focus on molecules containing aromatic ring‐like structures to develop our hypotheses. We also show that some drugs and anesthetics may have an effect on the lipid bilayer analogous to that of cholesterol.

show abstract

“…The bilayer partitioning and energy barriers faced in crossing the membrane have been determined from simulations for a variety of both perpetually neutral and protonatable compounds. These include benzocaine (35,(38)(39)(40), lidocaine (41,42), articaine (43), and phenytoin (35,40). All show that, irrespective of charge, compounds prefer partitioning into the bilayer from the aqueous phase to sit just under the lipid head groups, and they all face a barrier to pass through the hydrophobic bilayer core.…”

mentioning

confidence: 99%

Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels

Buyan

Sun

Corry

2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Voltage-gated sodium channels are essential for carrying electrical signals throughout the body, and mutations in these proteins are responsible for a variety of disorders, including epilepsy and pain syndromes. As such, they are the target of a number of drugs used for reducing pain or combatting arrhythmias and seizures. However, these drugs affect all sodium channel subtypes found in the body. Designing compounds to target select sodium channel subtypes will provide a new therapeutic pathway and would maximize treatment efficacy while minimizing side effects. Here, we examine the binding preferences of nine compounds known to be sodium channel pore blockers in molecular dynamics simulations. We use the approach of replica exchange solute tempering (REST) to gain a more complete understanding of the inhibitors' behavior inside the pore of NavMs, a bacterial sodium channel, and NavPas, a eukaryotic sodium channel. Using these simulations, we are able to show that both charged and neutral compounds partition into the bilayer, but neutral forms more readily cross it. We show that there are two possible binding sites for the compounds: () a site on helix 6, which has been previously determined by many experimental and computational studies, and () an additional site, occupied by protonated compounds in which the positively charged part of the drug is attracted into the selectivity filter. Distinguishing distinct binding poses for neutral and charged compounds is essential for understanding the nature of pore block and will aid the design of subtype-selective sodium channel inhibitors.

show abstract

Thermodynamic study of benzocaine insertion into different lipid bilayers

Cited by 24 publications

References 47 publications

From dioxin to dioxin congeners: understanding the differences in hydrophobic aggregation in water and absorption into lipid membranes by means of atomistic simulations

From dioxin to dioxin congeners: understanding the differences in hydrophobic aggregation in water and absorption into lipid membranes by means of atomistic simulations

Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes

Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels

Contact Info

Product

Resources

About