Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19.

Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak.

Surveying GPCR solubilisation conditions using surface plasmon resonance.

Biophysical screening techniques, such as surface plasmon resonance, enable detailed kinetic analysis of ligands binding to solubilised G-protein coupled receptors. The activity of a receptor solubilised out of the membrane is crucially dependent on the environment in which it is suspended. Finding the right conditions is challenging due to the number of variables to investigate in order to determine the optimum solubilisation buffer for any given receptor.

Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.

The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains.

Multi-Center Retrospective Evaluation of Screw and Polymethylmethacrylate Constructs for Atlantoaxial Fixation in Dogs.

Objective: To evaluate outcome and adverse events following ventral stabilization of the atlantoaxial (AA) joint in dogs with clinical AA subluxation using screw/polymethymethacrylate (PMMA) constructs in a retrospective, multi-center cohort study.

Study Design: Historical cohort study.

Animals: 35 client-owned dogs.

Application of RNAi to Genomic Drug Target Validation in Schistosomes.

Concerns over the possibility of resistance developing to praziquantel (PZQ), has stimulated efforts to develop new drugs for schistosomiasis. In addition to the development of improved whole organism screens, the success of RNA interference (RNAi) in schistosomes offers great promise for the identification of potential drug targets to initiate drug discovery. In this study we set out to contribute to RNAi based validation of putative drug targets.

Surface plasmon resonance analysis of seven-transmembrane receptors.

G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for around a third of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. Current receptor assay systems are based on measurement of either ligand displacement or downstream functional responses, rather than direct observation of ligand binding.

Fragment screening by SPR and advanced application to GPCRs.

Surface plasmon resonance (SPR) is one of the primary biophysical methods for the screening of low molecular weight 'fragment' libraries, due to its low protein consumption and 'label-free' methodology. SPR biosensor interaction analysis is employed to both screen and confirm the binding of compounds in fragment screening experiments, as it provides accurate information on the affinity and kinetics of molecular interactions. The most advanced application of the use of SPR for fragment screening is against membrane protein drug targets, such G-protein coupled receptors (GPCRs).

The Joint European Compound Library: boosting precompetitive research.

The Joint European Compound Library (JECL) is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation. The JECL has been established with a core of over 321,000 compounds from the proprietary collections of seven pharmaceutical companies and will expand to around 500,000 compounds. Here, we analyse the physicochemical profile and chemical diversity of the core collection, showing that the collection is diverse and has a broad spectrum of predicted biological activity.

Validity of ligand efficiency metrics.

A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem.

The role of ligand efficiency metrics in drug discovery.

The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.

Discovery of β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor.

G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. An alternative ligand discovery strategy is a fragment-based drug discovery, where low molecular weight compounds, known as fragments, are screened as initial starting points for optimization.

Automated design of ligands to polypharmacological profiles.

The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery.

Whole organism high-content screening by label-free, image-based Bayesian classification for parasitic diseases.

Sole reliance on one drug, Praziquantel, for treatment and control of schistosomiasis raises concerns about development of widespread resistance, prompting renewed interest in the discovery of new anthelmintics. To discover new leads we designed an automated label-free, high content-based, high throughput screen (HTS) to assess drug-induced effects on in vitro cultured larvae (schistosomula) using bright-field imaging. Automatic image analysis and Bayesian prediction models define morphological damage, hit/non-hit prediction and larval phenotype characterization.

Quantifying the chemical beauty of drugs.

Drug-likeness is a key consideration when selecting compounds during the early stages of drug discovery. However, evaluation of drug-likeness in absolute terms does not reflect adequately the whole spectrum of compound quality. More worryingly, widely used rules may inadvertently foster undesirable molecular property inflation as they permit the encroachment of rule-compliant compounds towards their boundaries.

Emerging role of surface plasmon resonance in fragment-based drug discovery.

Surface plasmon resonance (SPR) offers a method of biophysical fragment screening that is fast, efficient, cost effective and accurate. SPR is increasingly being adopted as a secondary assay to validate fragment hits. Recently, technical advances have resulted in the emergence of SPR as a primary screening methodology for fragment-based drug discovery.

Screening for GPCR Ligands Using Surface Plasmon Resonance.

G-protein coupled receptors (GPCRs) are a class of drug targets of primary importance. However, receptor assays are based on measurement of either ligand displacement or downstream functional responses, rather than direct observation of ligand binding. Issues of allosteric modulation, probe dependence, and functional selectivity create challenges in selecting suitable assays formats.

Rapid analysis of pharmacology for infectious diseases.

Pandemic, epidemic and endemic infectious diseases are united by a common problem: how do we rapidly and cost-effectively identify potential pharmacological interventions to treat infections? Given the large number of emerging and neglected infectious diseases and the fact that they disproportionately afflict the poorest members of the global society, new ways of thinking are required to developed high productivity discovery systems that can be applied to a larger number of pathogens. The growing availability of parasite genome data provides the basis for developing methods to prioritize, a priori, the potential drug target and pharmacological landscape of an infectious disease. Thus the overall objective of infectious disease informatics is to enable the rapid generation of plausible, novel medical hypotheses of testable pharmacological experiments, by uncovering undiscovered relationships in the wealth of biomedical literature and databases that were collected for other purposes.

Evaluation of treatment with a combination of azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology: 40 cases (2000-2007).

Objective: To evaluate outcome of treatment with a combination of azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology (MUE).

Design: Retrospective case series.

Animals: 40 dogs.

An ontology for description of drug discovery investigations.

The paper presents an ontology for the description of Drug Discovery Investigation (DDI).This has been developed through the use of a Robot Scientist "Eve", and in consultation with industry. DDI aims to define the principle entities and the relations in the research and development phase of the drug discovery pipeline.

Fragment screening by surface plasmon resonance.

Fragment-based drug discovery is a validated approach for the discovery of drug candidates. However, the weak affinity of fragment compounds requires highly sensitive biophysical techniques, such as nuclear magnetic resonance (NMR) or X-ray crystallography, to identify hits. Thus the advantages of screening small fragment libraries are partly offset by the high cost of biophysical analyses.

The tetrahydrobiopterin pathway and pain.

Novel approaches for treating chronic pain are required to address a widely recognized, yet largely underserved and unmet, clinical need. The recently discovered link between tetrahydrobiopterin (BH4) synthesis and pain in preclinical models and humans provides a promising new approach for treating neuropathic and other forms of chronic pain. The rate-limiting enzyme in BH4 synthesis, guanosine triphosphate cyclohydrolase 1 (GCH1), and sepiapterin reductase (SPR) are both promising drug targets based on initial active-site characterization of the SARs of these two enzymes.