A5002165980- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- DNA and Nucleic Acid Chemistry
- Neuropeptides and Animal Physiology
- Apelin-related biomedical research
- Genomics and Chromatin Dynamics
- Diet and metabolism studies
- Machine Learning in Materials Science
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Diabetes and associated disorders
- Pharmacological Receptor Mechanisms and Effects
- Angiogenesis and VEGF in Cancer
- Ion channel regulation and function
- Chemical Synthesis and Analysis
- Liver Disease Diagnosis and Treatment
- Neuroscience and Neuropharmacology Research
- DNA Repair Mechanisms
- Microbial Natural Products and Biosynthesis
- Nuclear Receptors and Signaling
- Lipid metabolism and disorders
- RNA Research and Splicing
- Fibroblast Growth Factor Research
- Cardiac electrophysiology and arrhythmias
Pfizer (United States)
2017-2022
Pfizer (United Kingdom)
2016-2018
University of Cambridge
2013-2017
Addenbrooke's Hospital
2015-2017
Papworth Hospital
2017
Imperial College London
2017
Unilever (United Kingdom)
2013-2015
Institute of Chemistry of Molecular Recognition
2010-2015
University College London
2015
Bury College
2015
Elabela/toddler (ELA) is a critical cardiac developmental peptide that acts through the G-protein-coupled apelin receptor, despite lack of sequence similarity to established ligand apelin. Our aim was investigate receptor pharmacology, expression pattern, and in vivo function ELA peptides adult cardiovascular system, seek evidence for alteration pulmonary arterial hypertension (PAH) which signaling downregulated, demonstrate attenuation PAH severity with exogenous administration rat model.In...
[Pyr(1)]apelin-13 is an endogenous vasodilator and inotrope but downregulated in pulmonary hypertension heart failure, making the apelin receptor attractive therapeutic target. Agonists acting at same G-protein-coupled can be engineered to stabilize different conformational states function as biased ligands, selectively stimulating either G-protein or β-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions design cyclic analogues identified MM07 a agonist....
The DNA Polymerase α (Pol α)/primase complex initiates synthesis in eukaryotic replication. In the complex, Pol and primase cooperate production of RNA-DNA oligonucleotides that prime new DNA. Here we report crystal structures catalytic core yeast unliganded form, bound to an RNA primer/DNA template extending primer with deoxynucleotides. We combine structural analysis biochemical computational data demonstrate specifically recognizes A-form RNA/DNA helix ensuing B-form terminates synthesis....
The capability to rank different potential drug molecules against a protein target for potency has always been fundamental challenge in computational chemistry due its importance design. While several simulation-based methodologies exist, they are hard use prospectively and thus predicting lead optimization campaigns remains an open challenge. Here we present the first machine learning approach specifically tailored ranking congeneric series based on deep 3D-convolutional neural networks....
Notch is a conserved signaling pathway that specifies cell fates in metazoans. Receptor-ligand interactions induce changes gene expression, which regulated by the transcription factor CBF1/Su(H)/Lag-1 (CSL). CSL interacts with coregulators to repress and activate from target genes. While molecular details of activator complex are relatively well understood, structure-function CSL-mediated repressor complexes poorly defined. In Drosophila, antagonist Hairless directly binds Su(H) (the fly...
Valproic acid (VPA) is an anticonvulsant drug that also used to treat migraines and bipolar disorder. Its proposed biological targets include human voltage-gated sodium channels, among other membrane proteins. We the prokaryotic NavMs channel, which has been shown be a good exemplar for binding examine structural functional interactions of VPA. Thermal melt synchrotron radiation circular dichroism spectroscopic studies full-length channel (which includes both pore voltage sensor domains),...
The development of G protein-biased agonists for the μ-opioid receptor (MOR) offers a clear drug discovery rationale improved analgesia and reduced side-effects opiate pharmacotherapy. However, our understanding molecular mechanisms governing ligand bias is limited, which hinders ability to rationally design biased compounds. We have investigated role MOR binding site residues W320 Y328 in controlling bias, by mutagenesis. pharmacology panel ligands cAMP β-arrestin2 assay were compared...
Modulating protein activity with small-molecules binding to cryptic pockets offers great opportunities overcome hurdles in drug design. Cryptic sites are atypical proteins that closed the absence of a stabilizing ligand and thus inherently difficult identify. Many studies have proposed methods predict sites. However, general approach prospectively sample open conformations these identify an unbiased manner suitable for structure-based design remains elusive. Here, we describe all-atom,...
Fibroblast growth factors (FGFs) are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation a ternary complex with transmembrane tyrosine kinase receptors (FGFRs), and heparan sulphate proteoglycans (HSPGs) is required FGF2 pro-angiogenic activity. Here by using combination techniques Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance cell-based binding assays we clarify molecular mechanism inhibition...
Metabolism of xenobiotic and endogenous compounds is frequently complex, not completely elucidated, therefore often ambiguous. The prediction sites metabolism (SoM) can be particularly helpful as a first step toward the identification metabolites, process especially relevant to drug discovery. This paper describes reactivity approach for predicting SoM whereby derived directly from ground state ligand molecular orbital analysis, calculated using Density Functional Theory, novel...
Allostery describes the functional coupling between sites in biomolecules. Recently, role of changes protein dynamics for allosteric communication has been highlighted. A quantitative and predictive description allostery is fundamental understanding biological processes. Here, we integrate an ensemble-based perturbation approach with analysis biomolecular rigidity flexibility to construct a model dynamic allostery. Our model, by definition, excludes possibility conformational changes,...
Biased agonists, which selectively stimulate certain signaling pathways controlled by a G protein-coupled receptor (GPCR), hold great promise as drugs that maximize efficacy while minimizing dangerous side effects. agonists of the μ-opioid (μOR) are particular interest means to achieve analgesia through protein without dose-limiting effects such respiratory depression and constipation. Rational structure-based design biased remains highly challenging, however, because ligand-mediated...
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...
Regulation of transcription is fundamental to development and physiology, occurs through binding factors specific DNA sequences in the genome. CSL (CBF1/Suppressor Hairless/LAG-1), a core component Notch signaling pathway, one such factor that acts concert with co-activators or co-repressors control activity associated target genes. One question how can recognize select among different available vivo whether variations between selected influence its function. We have therefore investigated...
Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission a rational therapeutic approach for variety neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons critically mediated by sodium- pH-dependent high-affinity transporter (CHT, encoded SLC5A7 gene). This comparatively...
Abstract Background Protein-DNA recognition underlies fundamental biological processes ranging from transcription to replication and modification. Herein, we present a computational study of the sequence modulation internal dynamic properties intraprotein networks aminoacid interactions that determine stability specificity protein-DNA complexes. Results To this aim, apply novel theoretical approaches analyze dynamics energetics systems starting MD trajectories. As model system, chose...
The value of including protein flexibility in structure-based drug design (SBDD) is widely documented, and currently, molecular dynamics (MD) simulations represent a powerful tool to investigate dynamics. Yet, the inclusion MD-derived information pre-existing SBDD workflows still far from trivial. We recently published an integrated MD-FLAP (Fingerprints for Ligands Proteins) approach combining MD, clustering Linear Discriminant Analysis (LDA) enhancing accuracy, efficacy, conformational...
The availability of large chemical libraries containing hundreds millions to billions diverse drug-like molecules combined with an almost unlimited amount compute power achieve scientific calculations has led investors and researchers have a renewed interest in virtual screening (VS) methods identify biologically active compounds. number silico tools software which employ the knowledge protein target or known bioactive ligands is increasing at rapid pace, creating crowded computational...
The capability to rank different potential drug molecules against a protein target for potency has always been fundamental challenge in computational chemistry due its importance design. While several simulation-based methodologies exist, they are hard use prospectively and thus predicting lead optimization campaigns remains an open challenge. Here we present the first machine learning approach specifically tailored ranking congeneric series based on deep 3D-convolutional neural networks....