A relationship between membrane permeation and partitioning of nitroaromatic explosives and their functional groups. A computational study

Yang, Hong; Li, Huarong; Zhou, Mi; Wei, Tong; Tang, Can; Liu, Liu; Zhou, Yang; Long, Xinping

doi:10.1039/d0cp00549e

Cited by 6 publications

(10 citation statements)

References 60 publications

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“…Antiseptic Picloxydine, Octenidine, Miramistin [470], Polyhexamethylene Biguanide [471] Insecticide Parathione [132], Fipronil [472], Dibutyl succinate [203] Former Drugs d-sotalol, cisapride [473], piracetam (status varies among countries) [474], ORG-12962 [199] Toxic xenobiotic Polybrominated-diphenyl-ethers [475], Bisphenol [476], Perfluoroalkyls [477], nitroaromatic explosives (TNT,2A, and 24DA) [478][479][480][481], 1,4-Dioxane [482], Benzo[a]pyrene [483] Nanomaterials Graphene [484][485][486][487], Carbon Dots [488], Phosphorene Oxide Nanosheets [489], Gold Nanoparticles [490][491][492], Titanium Dioxide Nanoparticles [493], Generic Nanoparticles (coarse grained) [494], Fullerene [495][496][497][498], Previous reviews [499] Polymers Poly(ethyleneoxide)-Poly-(propylene oxide) [500], polyethylenimine [501], Poloxamer [502,503], Pluronics [504,505], poly(ethyleneglycol)-desferrioxamine/ gallium [506], PEG functionalized with carbochydrates [507] and peptides…”

Section: Application Xenobioticmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Application Xenobioticmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…First, hydrogen bonding between each of the drugs and water molecules was analyzed (Figure S10), as the impact of hydrogen bonding on permeation efficiency was previously reported in multiple studies. 11,62 It was shown that, generally, the larger the number of hydrogen bonds with water, the lower the permeation rate across the membrane, as the loss of hydrogen bonds between the permeant and water molecules results in an energetic penalty for the permeation pathway.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Yang et al . explored the influence of different functional groups on the permeation of nitroaromatic compounds, finding that the hydrogen bonding ability of the molecules is related to the permeability: the addition of polar groups decreases the permeability …”

Section: Introductionmentioning

confidence: 99%

Modeling the Effect of Hydrophobicity on the Passive Permeation of Solutes across a Bacterial Model Membrane

Sousa

Kamal

Richter

et al. 2022

J. Chem. Inf. Model.

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Passive diffusion across biomembranes is an important mechanism of permeation for multiple drugs, including antibiotics. However, this process is frequently neglected while studying drug uptake and, in our view, warrants further investigation. Here, we apply molecular dynamics simulations to investigate the impact of changes in molecular hydrophobicity on the permeability of a series of inhibitors of the quorum sensing of Pseudomonas aeruginosa, previously discovered by us, across a membrane model. Overall, we show that permeation across this membrane model does not correlate with the molecule's hydrophobicity. We demonstrate that using a simple model for permeation, based on the difference between the maximum and minimum of the free energy profile, outperforms the inhomogeneous solubility-diffusion model, yielding a permeability ranking that better agrees with the experimental results, especially for hydrophobic permeants. The calculated differences in permeability could not explain differences in in bacterio activity. Nevertheless, substantial differences in molecular orientation along the permeation pathway correlate with the in bacterio activity, emphasizing the importance of analyzing, at an atomistic level, the permeation pathway of these solutes.

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“…The force constant of the harmonic spring was 1000 kJ mol –1 nm –2 for all windows, ensuring the adequate sampling of the simulations. Each window was run for 50 ns and the last 20 ns of trajectories were used for the calculation of PMF profiles . Due to membrane symmetry, we only calculated the free energy profiles from z = 4 nm to z = 0 nm.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous work found that the monoamino metabolites of TNT had higher transmembrane capacity than their parent compound, which helps to explain why they are even more toxic than TNT . It is still a challenge for experimental techniques to obtain a detailed molecular-level understanding of chemical–membrane interactions, and molecular simulation technology has been proved to be a useful tool for obtaining information about the penetration and distribution of small molecules in cell membranes and how they affect the properties of lipid bilayer membranes. ,, In the present work, we used the all-atom molecular dynamics (MD) method and umbrella sampling (US) technology to study the permeation process of RDX and DNAN mixtures, according to their molar ratio within IMX-104 formulation, from the water phase to the 1-palmitoyl-2-oleoyl- sn- glycerol-3-phosphocholine (POPC) phospholipid bilayer membrane, and investigate the effect of intermolecular interaction between RDX and DNAN on their entering into the membrane.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Effects of IMX-104 Components in Membrane Absorption: A Computational Study

Yang

Zhou

et al. 2022

ACS Omega

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New insensitive munitions such as IMX-104 formulations are being developed to improve the safety suffering from accidental stimulations. Experimental data indicated the synergistic toxicity of 2,4-dinitroanisole (DNAN) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in IMX-104, which increased the concern about its environmental and health threats. Indeed, little is known about the synergistic mechanism. Here, we investigated the membrane absorption of DNAN and RDX as the first step toward uncovering synergistic toxicity. The permeability coefficient, transmembrane time, and liposome–water partition coefficient were calculated by the umbrella sampling technique. The results show that component RDX in the IMX-104 formulation promotes the membrane absorption of another more toxic component DNAN, suggesting that the synergistic toxicity effect of IMX-104 may emerge from their membrane adsorption stage. In detail, the integrating free-energy curves show that DNAN, RDX, or their mixture in membranes would promote subsequent molecules passing through membranes. For the mixture of DNAN and RDX, RDX was absorbed by the membrane before DNAN. Postabsorbed DNAN tends to stay around RDX, which is due to the strong van der Waals (VDW) interaction between them. RDX stabilized under phospholipid headgroups limits the overflow of DNAN from the membrane, which results in 11% more absorption of DNAN by the membrane than in the case of the pure DNAN system.

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A relationship between membrane permeation and partitioning of nitroaromatic explosives and their functional groups. A computational study

Abstract: Nitroaromatic explosives, such as 2,4,6-trinitrotoluene, are representative aromatic compounds, which are generally highly toxic.

Cited by 6 publications

References 60 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Modeling the Effect of Hydrophobicity on the Passive Permeation of Solutes across a Bacterial Model Membrane

Synergistic Effects of IMX-104 Components in Membrane Absorption: A Computational Study

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