Small-Molecule Lipid-Bilayer Anion Transporters for Biological Applications

2013 ◽  
Vol 52 (5) ◽  
pp. 1374-1382 ◽  
Author(s):  
Nathalie Busschaert ◽  
Philip A. Gale
Keyword(s):  
Lipid Bilayer ◽  
Small Molecule ◽  
Biological Applications ◽  
Anion Transporters

Increasing membrane permeability of carboxylic acid-containing drugs using synthetic transmembrane anion transporters

2021 ◽  
Author(s):  
Rayhanus Salam ◽  
Surid Mohammad Chowdhury ◽  
Sarah Ruth Marshall ◽  
Hassan Gneid ◽  
Nathalie Busschaert
Keyword(s):  
Carboxylic Acid ◽  
Membrane Permeability ◽  
Lipid Bilayers ◽  
Small Molecule ◽  
Anion Transporters

In this manuscript, we show that small-molecule-based anion transporters can significantly increase the permeability of carboxylic acid containing drugs across lipid bilayers of model vesicles. Due to the drug-like characteristics...

Biological applications of synthetic anion transporters

2020 ◽  
Vol 56 (91) ◽  
pp. 14137-14153 ◽  
Author(s):  
Nasim Akhtar ◽  
Oindrila Biswas ◽  
Debasis Manna
Keyword(s):  
Small Molecules ◽  
Cancer Cells ◽  
Transmembrane Transport ◽  
Biological Applications ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
Anion Transporters

Transmembrane transport of anions by small molecules has recently been used to reduce the viability of cancer cells and fight against antibiotic-resistant and clinically relevant bacterial strains.

scholarly journals Small molecule‐facilitated anion transporters in cells for a novel therapeutic approach to cystic fibrosis

2019 ◽  
Vol 176 (11) ◽  
pp. 1764-1779 ◽  
Author(s):  
Michele Fiore ◽  
Claudia Cossu ◽  
Valeria Capurro ◽  
Cristiana Picco ◽  
Alessandra Ludovico ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecule ◽  
Therapeutic Approach ◽  
Anion Transporters ◽  
Novel Therapeutic ◽  
In Cells

scholarly journals Small molecule anion transporters display in vitro antimicrobial activity against clinically relevant bacterial strains

2019 ◽  
Vol 55 (68) ◽  
pp. 10080-10083 ◽  
Author(s):  
Israel Carreira-Barral ◽  
Carlos Rumbo ◽  
Marcin Mielczarek ◽  
Daniel Alonso-Carrillo ◽  
Enara Herran ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Small Molecule ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
In Vitro Antimicrobial Activity ◽  
Anion Transporters ◽  
Highly Active

Highly active transmembrane anion transporters have demonstrated their activity against antibiotic-resistant and clinically relevant bacterial strains.

scholarly journals Rational design of small molecule fluorescent probes for biological applications

2020 ◽  
Vol 18 (30) ◽  
pp. 5747-5763 ◽  
Author(s):  
Joomyung V. Jun ◽  
David M. Chenoweth ◽  
E. James Petersson
Keyword(s):  
Energy Transfer ◽  
Small Molecule ◽  
Fluorescent Probes ◽  
Rational Design ◽  
Biological Systems ◽  
Biological Applications

Guidelines based on photophysical tuning, reactivity, isomerization, and energy transfer for rational design of synthetic fluorescent probes for biological systems.

scholarly journals Small-Molecule Photostabilizing Agents are Modifiers of Lipid Bilayer Properties

2013 ◽  
Vol 104 (11) ◽  
pp. 2410-2418 ◽  
Author(s):  
Jose L. Alejo ◽  
Scott C. Blanchard ◽  
Olaf S. Andersen
Keyword(s):  
Lipid Bilayer ◽  
Small Molecule

scholarly journals Allosteric Role of Substrate Occupancy Toward the Alignment of P-glycoprotein Nucleotide Binding Domains

2018 ◽  
Author(s):  
Lurong Pan ◽  
Stephen G Aller
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Lipid Bilayer ◽  
Small Molecule ◽  
Aromatic Amino Acids ◽  
Drug Binding ◽  
Atp Binding ◽  
Binding Domains ◽  
P Glycoprotein ◽  
Binding Cavity

AbstractP-glycoprotein (Pgp) is an ATP-binding cassette transporter that eliminates toxins from the cell but causes multidrug resistance in chemotherapies. The crystal structures of Pgp revealed drug-like compounds bound to an inward-facing conformation in which the energy-harnessing nucleotide binding domains (NBDs) were widely separated with no interfacial interaction. Following drug binding, inward-facing Pgp must transition to an NBD dimer conformation to achieve ATP binding and hydrolysis at canonical sites defined by both halves of the interface. However, given the high degree of flexibility shown for this transporter, it is difficult to envision how NBDs overcome entropic considerations for achieving proper alignment in order to form the canonical ATP binding site. We explored the hypothesis that substrate occupancy of the polyspecific drug-binding cavity plays a role in the proper alignment of NBDs using computational approaches. We conducted twelve atomistic molecular dynamics (MD) simulations (100-300 ns) on inward-facing Pgp in a lipid bilayer with and without small molecule substrates to ascertain effects of drug occupancy on NBD dimerization. Both apo- and drug-occupied simulations showed NBDs approaching each other compared to the crystal structures. Apo-Pgp reached a pseudo-dimerization in which NBD signature motifs for ATP binding exhibited a significant misalignment during closure. In contrast, occupancy of three established substrates positioned by molecular docking achieved NBD alignment that was much more compatible with a canonical NBD dimerization trajectory. Additionally, aromatic amino acids, known to confer the polyspecific drug-binding characteristic of the internal pocket, may also govern polyspecific drug access to the cavity. The enrichment of aromatics comprising the TM4-TM6 portal suggested a preferential pathway over the aromatic-poor TM10-TM12 for lateral drug entry from the lipid bilayer. Our study also suggested that drug polyspecificity is enhanced due to a synergism between multiple drug-domain interactions involving 36 residues identified in TM1, 5, 6, 7, 11 and 12.Author SummaryP-glycoprotein (Pgp) is an active drug pump known to cause clinical multi-drug resistance. The static atomic structure of Pgp was determined by trapping an inward-facing conformation bound to small molecule substrates by crystallization, however the effect of substrates on Pgp dynamics following binding is poorly understood. In this study, six apo-Pgp and six drug-occupied Pgp were simulated using unconstrained atomistic molecular dynamics (MD) for 100-300 ns. We demonstrate an allosteric communication of drug binding “from the top down”, that is from the TMDs to the NBDs that promotes NBD alignment and trajectories that favor canonical ATP binding. Other analyses suggested that aromatic amino acids in both the central drug-binding cavity and the “front portal” (TM4/TM6) confer polyspecific recognition. Additionally, comparison of the thermal B-factors between the experimental measurement and MD simulation indicated that different physical and chemical environments (temperature, in surfo vs. in meso, solution compositions) only alter the regional scales of thermal fluctuations but not the patterns of these motions. Lastly, DCCM and normal mode analyses were used to decipher thermal motions and the motion correlations between various domains in Pgp, allowing us to propose a substrate allosteric mechanism and an energy conservation mechanism during the catalytic cycle.

scholarly journals Self‐Assembly of Protein‐Containing Lipid‐Bilayer Nanodiscs from Small‐Molecule Amphiphiles

Small ◽  
2021 ◽  
pp. 2103603
Author(s):  
Florian Mahler ◽  
Annette Meister ◽  
Carolyn Vargas ◽  
Grégory Durand ◽  
Sandro Keller
Keyword(s):  
Lipid Bilayer ◽  
Small Molecule ◽  
Self Assembly
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