Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells.

Objectives: The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear.

Identification of Ribonuclease Inhibitors for the Control of Pathogenic Bacteria.

Bacteria are known to be constantly adapting to become resistant to antibiotics. Currently, efficient antibacterial compounds are still available; however, it is only a matter of time until these compounds also become inefficient. Ribonucleases are the enzymes responsible for the maturation and degradation of RNA molecules, and many of them are essential for microbial survival.

Using site-directed mutagenesis to further the understanding of insulin receptor-insulin like growth factor-1 receptor heterodimer structure.

Type 2 diabetes is characterised by the disruption of insulin and insulin-like growth factor (IGF) signalling. The key hubs of these signalling cascades - the Insulin receptor (IR) and Insulin-like growth factor 1 receptor (IGF1R) - are known to form functional IR-IGF1R hybrid receptors which are insulin resistant. However, the mechanisms underpinning IR-IGF1R hybrid formation are not fully understood, hindering the ability to modulate this for future therapies targeting this receptor.

Mapping the functional impact of non-coding regulatory elements in primary T cells through single-cell CRISPR screens.

Background: Drug targets with genetic evidence are expected to increase clinical success by at least twofold. Yet, translating disease-associated genetic variants into functional knowledge remains a fundamental challenge of drug discovery. A key issue is that the vast majority of complex disease associations cannot be cleanly mapped to a gene.

From O/GABA-AT, GABA, and T-263 Mutant to Conception of .

causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find ornithine aminotransferase (OAT) is conserved across phyla. We solve O/GABA-AT structures with bound inactivators at 1.

Developments in Non-Intercalating Bacterial Topoisomerase Inhibitors: Allosteric and ATPase Inhibitors of DNA Gyrase and Topoisomerase IV.

Increases in antibiotic usage and antimicrobial resistance occurrence have caused a dramatic reduction in the effectiveness of many frontline antimicrobial treatments. Topoisomerase inhibitors including fluoroquinolones are broad-spectrum antibiotics used to treat a range of infections, which stabilise a topoisomerase-DNA cleavage complex via intercalation of the bound DNA. However, these are subject to bacterial resistance, predominantly in the form of single-nucleotide polymorphisms in the active site.

design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region.

By 2050, it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, more deaths than cancer, costing the world economy $100 trillion. Clearly, strategies to address this problem are essential as bacterial evolution is rendering our current antibiotics ineffective. The discovery of an allosteric binding site on the established antibacterial target DNA gyrase offers a new medicinal chemistry strategy.

Recent developments in the structural characterisation of the IR and IGF1R: implications for the design of IR-IGF1R hybrid receptor modulators.

The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are dimeric disulfide-linked receptor tyrosine kinases, whose actions regulate metabolic and mitogenic signalling pathways inside the cell. It is well documented that in tissues co-expressing the IR and IGF1R, their respective monomers can heterodimerise to form IR-IGF1R hybrid receptors. Increased populations of the IR-IGF1R hybrid receptors are associated with several disease states, including type 2 diabetes and cancer.

From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor.

Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor.

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity.

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from .

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections.

Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated K1.1 (KCNT1) Potassium Channel.

Drug-resistant epileptic encephalopathies of infancy have been associated with KCNT1 gain-of-function mutations, which increase the activity of K1.1 sodium-activated potassium channels. Pharmacological inhibition of hyperactive K1.

Fibrinogen interaction with complement C3: a potential therapeutic target to reduce thrombosis risk.

Complement C3 binds fibrinogen and compromises fibrin clot lysis thereby enhancing thrombosis risk. We investigated the role of fibrinogen-C3 interaction as a novel therapeutic target to reduce thrombosis risk by analysing: i) consistency in the fibrinolytic properties of C3, ii) binding sites between fibrinogen and C3 and iii) modulation of fibrin clot lysis by manipulating fibrinogen-C3 interactions. Purified fibrinogen and C3 from the same individuals (n=24) were used to assess inter-individual variability in the anti-fibrinolytic effects of C3.

Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment.

Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in . malaria. Yet only few nonphosphorus inhibitors have been reported so far.

Author Correction: New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase.

Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high-resolution X-ray crystal structures of the and seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than 2 orders of magnitude compared to their human homologue, demonstrating a route to the selective chemical inhibition of these bacterial targets.

New insights into the binding mode of pyridine-3-carboxamide inhibitors of E. coli DNA gyrase.

Previously we have reported on a series of pyridine-3-carboxamide inhibitors of DNA gyrase and DNA topoisomerase IV that were designed using a computational de novo design approach and which showed promising antibacterial properties. Herein we describe the synthesis of additional examples from this series aimed specifically at DNA gyrase, along with crystal structures confirming the predicted mode of binding and in vitro ADME data which describe the drug-likeness of these compounds.

Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates.

Background: The β-lactam antibiotics represent the most successful drug class for treatment of bacterial infections. Resistance to them, importantly via production of β-lactamases, which collectively are able to hydrolyse all classes of β-lactams, threatens their continued widespread use. Bicyclic boronates show potential as broad spectrum inhibitors of the mechanistically distinct serine- (SBL) and metallo- (MBL) β-lactamase families.

Structure-switching ML Ir(iii) coordination cages with photo-isomerising azo-aromatic linkers.

Cyclotriguaiacylene has been functionalised with 3- or 4-pyridyl-azo-phenyl groups to form a series of molecular hosts with three azobenzene-type groups that exhibit reversible photo-isomerisation. Reaction of the host molecules with [Ir(C^N)(NCMe)] where C^N is the cyclometallating 2-phenylpyridinato, 2-(4-methylphenyl)pyridinato or 2-(4,5,6-trifluorophenyl)pyridinato results in the self-assembly of a family of five different [{Ir(C^N)}(L)] coordination cages. Photo-irradiation of each of the cages with a high energy laser results in → photo-isomerisation of the pyridyl-azo-phenyl groups with up to 40% of groups isomerising.

CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in .

, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized.

Identification of a small molecule inhibitor of Ebola virus genome replication and transcription using in silico screening.

Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen.

X-ray and cryo-EM structures of inhibitor-bound cytochrome complexes for structure-based drug discovery.

Cytochrome , a dimeric multi-subunit electron-transport protein embedded in the inner mitochondrial membrane, is a major drug target for the treatment and prevention of malaria and toxoplasmosis. Structural studies of cytochrome from mammalian homologues co-crystallized with lead compounds have underpinned structure-based drug design to develop compounds with higher potency and selectivity. However, owing to the limited amount of cytochrome that may be available from parasites, all efforts have been focused on homologous cytochrome complexes from mammalian species, which has resulted in the failure of some drug candidates owing to toxicity in the host.

In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors.

Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases.

Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led Design.

Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a -based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1.

Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action.

Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on macrophages and natural killer cells) and FcγRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets.