MolMeDB: Molecules on Membranes Database

Juračka, Jakub; Šrejber, Martin; Melíková, Michaela; Bazgier, Václav; Berka, Karel

doi:10.1093/database/baz078

Cited by 15 publications

(13 citation statements)

References 40 publications

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“…Notably the free-energy profile shows a very steep decrease in free energy from the center of the bilayer out to Z ∼ 12 Å. The profiles presented here suggest that caffeine is more unfavorable deep in the bilayer than that reported in previous studies. , …”

Section: Resultssupporting

confidence: 47%

“…The profiles presented here suggest that caffeine is more unfavorable deep in the bilayer than that reported in previous studies. 17,65 Additional free-energy profiles were calculated for two beta blocker molecules, pindolol and alprenolol, as well as the NSAID ibuprofen. These compounds contain a wider range of chemical group types along with significant conformational flexibility and ionizable groups.…”

mentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 47%

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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show abstract

“…The permeation barrier considered was therefore not the whole membrane, but rather the non-polar membrane centre between the two leaflets. This is in agreement with the results obtained for the energy profile of drug-like molecules across lipid membranes, which usually shows a minimum at each membrane leaflet and an energy barrier at the membrane centre [ 30 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

Section: Discussionsupporting

confidence: 92%

Calculation of Permeability Coefficients from Solute Equilibration Dynamics: An Assessment of Various Methods

2022

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Predicting the rate at which substances permeate membrane barriers in vivo is crucial for drug development. Permeability coefficients obtained from in vitro studies are valuable for this goal. These are normally determined by following the dynamics of solute equilibration between two membrane-separated compartments. However, the correct calculation of permeability coefficients from such data is not always straightforward. To address these problems, here we develop a kinetic model for solute permeation through lipid membrane barriers that includes the two membrane leaflets as compartments in a four-compartment model. Accounting for solute association with the membrane allows assessing various methods in a wide variety of conditions. The results showed that the often-used expression Papp= β × r/3 is inapplicable to very large or very small vesicles, to moderately or highly lipophilic solutes, or when the development of a significant pH gradient opposes the solute’s flux. We establish useful relationships that overcome these limitations and allow predicting permeability in compartmentalised in vitro or in vivo systems with specific properties. Finally, from the parameters for the interaction of the solute with the membrane barrier, we defined an intrinsic permeability coefficient that facilitates quantitative comparisons between solutes.

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“…In another impressive study, Natesan et al, proposed a theoretical method based on drug structure that allowed for the prediction of the location of drug molecules within the bilayer [151]; this work was performed using experimental results of 107 separate small molecules interacting with lipid membranes. An extensive database was compiled that contains over 3600 cases of compound-membrane interactions gathered from both experimental and theoretical studies, known as the "Molecules on Membranes Database" (MolMeDB), [152]; MolMeDB provides data concerning drug-membrane partitioning, penetration, and positioning.…”

Section: Location and Orientation Of Drug Molecules In The Lipid Bilayermentioning

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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MolMeDB: Molecules on Membranes Database

Cited by 15 publications

References 40 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

Calculation of Permeability Coefficients from Solute Equilibration Dynamics: An Assessment of Various Methods

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

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