A5048035973- Drug Transport and Resistance Mechanisms
- Protein Interaction Studies and Fluorescence Analysis
- Cancer, Hypoxia, and Metabolism
- Ion channel regulation and function
- Lipid Membrane Structure and Behavior
- Advanced NMR Techniques and Applications
- Advancements in Transdermal Drug Delivery
- Ion Channels and Receptors
- Protein Structure and Dynamics
- Metabolomics and Mass Spectrometry Studies
- Mitochondrial Function and Pathology
- Immune cells in cancer
- Cardiac electrophysiology and arrhythmias
- Surfactants and Colloidal Systems
- Epigenetics and DNA Methylation
- Bioactive Compounds and Antitumor Agents
- Hemoglobin structure and function
- Advanced Glycation End Products research
- Spectroscopy and Quantum Chemical Studies
- Fibroblast Growth Factor Research
- Nanopore and Nanochannel Transport Studies
- Fuel Cells and Related Materials
- Nanoparticle-Based Drug Delivery
- Collagen: Extraction and Characterization
- Grouting, Rheology, and Soil Mechanics
University of Portsmouth
2025
Aarhus University
2022-2025
Johns Hopkins University
2019-2023
Georgetown University
2021-2022
King's College London
2015-2020
King's College - North Carolina
2018
Transnational Press London
2017
University of Oxford
2015
Trinity House
2015
Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis deoxyribonucleotide triphosphates (dNTPs). However, oxygen an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us question source dNTPs in hypoxia. Here, we show that RRM1/RRM2B retaining activity therefore favored over RRM1/RRM2 order preserve ongoing avoid...
Abstract Drug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to difficulty crossing blood-brain barrier (BBB). Here we develop and experimentally validate a new silico method predict quantitatively BBB permeability small-molecule drugs. We show accurate prediction solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations spontaneous drug diffusion across...
Elhanafy et al. used Molecular Dynamics simulations and electrophysiology to show how identical mutations in the volgage sending domain of sodium channels can yield differential functional effects.
Collagen is the single most abundant protein in extracellular matrix animal kingdom, with remarkable structural and functional diversity regarded one of useful biomaterials. Etymologically, term collagen comes from Greek kola 'glue' gen 'giving birth to'. Thus, it not surprising that various collagens structures they form all serve same purpose, to help tissues withstand stretching. Among functions are involved cell adhesion migration, tissue repair, scaffolding morphogenesis. Thus knowledge...
The binding of prolyl-hydroxylated HIF-α to PHD2 is hindered by prior 2OG binding; likely, leading the inhibition degradation under limiting conditions.
The chronic response of animals to hypoxia is mediated by the αβ-heterodimeric hypoxia-inducible transcription factors (α,β-HIFs) which upregulate expression sets genes that work ameliorate effects limiting dioxygen. HIF prolyl hydroxylase domain enzymes (PHDs) are Fe(II)- and 2-oxoglutarate-dependent oxygenases act as hypoxia-sensing components system: prolyl-hydroxylation signals for dioxgen availability-dependent HIF-α degradation via ubiquitin proteasome system. unusual kinetic...
Potassium channels are of paramount physiological and pathological importance therefore constitute significant drug targets. One the keys to rationalize way drugs modulate ion is understand ability such small molecules access their respective binding sites, from which they can exert an activating or inhibitory effect. Many computational studies have probed energetics permeation, mechanisms voltage gating, but little known about role fenestrations as possible mediators entry in potassium...
<sup>13</sup>C-NMR spectroscopy is a valuable tool for investigating the mechanisms of inhibitors clinically relevant OXA β-lactamases.
2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and readily detected in tissues healthy individuals. 2HG found two enantiomeric forms: S-2HG R-2HG. Here, we investigate differential roles these enantiomers cluster differentiation (CD)8+ T cell biology, where find they have highly divergent effects on proliferation, differentiation, function. We show here an analysis structural determinants that likely underlie specific α-ketoglutarate (αKG)-dependent enzymes....
Voltage-gated potassium channels of the Kv1 family play a crucial role in generation and transmission electrical signals excitable cells affecting neuronal cardiac activities. Small-molecule blockage these has been proposed to occur via cooperative mechanism involving two main blocking sites: inner-pore site located below selectivity filter, side-pocket cavity between pore voltage sensor. Using 0.5 μs molecular dynamics simulation trajectories complemented by docking calculations, potential...
The treatment of various disorders the central nervous system (CNS) is often impeded by limited brain exposure drugs, which regulated human blood-brain barrier (BBB). screening lead compounds for CNS penetration challenging due to biochemical complexity BBB, while experimental determination permeability not feasible all types compounds. Here we present a novel method rapid preclinical libraries utilizing advancements in computing hardware, with its foundation transition-based counting flux....
We report molecular dynamics simulations of rhodamine entry into the central binding cavity P-gp in inward open conformation. Rhodamine can enter inner volume via passive transport across luminal membrane or lateral diffusion lipid bilayer. Entry is determined by aperture angle at apex protein, with a critical 27° for rhodamine. The has an aqueous phase few lipids, which significantly reduces substrate diffusion. Within cavity, we identified regions relatively weak binding, suggesting that...
The blood-brain barrier remains a major roadblock to the delivery of drugs brain. While in vitro and vivo measurements permeability are widely used predict brain penetration, very little is known about mechanisms passive transport. Detailed insight into interactions between solutes cell membranes could provide new drug design screening. Here, we perform unbiased atomistic MD simulations visualize translocation library 24 across lipid bilayer representative microvascular endothelial cells. A...
It has been proposed that general anesthesia results from direct multisite interactions with multiple and diverse ion channels in the brain. An understanding of mechanisms by which anesthetics modulate is essential to clarify their underlying behavior role reversible immobilization amnesia. Despite fact volatile are drugs primarily induce insensitivity pain, they have reported sensitize active vanilloid-1 receptor, TRPV1, known mediate response nervous system certain harmful stimuli plays a...
The hypoxia-inducible transcription factors (HIF) play a central role in the human oxygen sensing signaling pathway. binding of von Hippel–Lindau tumor suppressor protein (pVHL)–ElonginC–ElonginB complex (VCB) to HIF-1α is highly selective for trans-4-hydroxylation form when Pro564 C-terminal oxygen-dependent degradation domain (ODDD) HIF-1α. HIFα VCB increased by ∼1000-fold upon addition single hydroxyl group either two conserved proline-residues. Here, we address how this governs...
SUMMARY 2-hydroxyglutarate (2HG) is a by-product of the TCA cycle, and readily detected in tissues healthy individuals. 2HG found two enantiomeric forms: S-2HG R-2HG. Here, we investigate differential roles these enantiomers CD8+ T cell biology, where they had highly divergent effects on proliferation, differentiation, function. We show here an analysis structural determinants that likely underlie specific a-ketoglutarate (aKG)-dependent enzymes. Treatment cells with exogenous S-2HG, but not...