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Malaria is a devastating infection caused by protozoa of the genus Plasmodium . Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline’s chemical library for inhibitors of P. falciparum , of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 µM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease. Antimalarial arsenal There are still nearly 250 million malaria cases reported annually, over 800,000 fatal, with most deaths being children under 5. The malaria parasite Plasmodium falciparum is notoriously adept at developing drug resistance, and new drugs are urgently needed. Two reports raise hopes that alternatives to artemisinins might be found, by identifying thousands of compounds inhibiting the growth of P. falciparum asexual-stage parasites in red blood cells, many distinct in structure and mechanism from current drugs. Guiguemde et al . present a chemical genomics screen of over 300,000 compounds: the 1,300 'hits' include 561 with good potency and broad therapeutic windows. Gamo et al . screened nearly 2 million compounds from GlaxoSmithKline's chemicals library, finding over 13,500 hits, many active against multidrug-resistant isolates. These studies provide a rich source of potential leads, freely available to academic and industry labs looking for new antimalarials. Here, nearly 2 million compounds from GlaxoSmithKline's chemical library were screened for inhibitors of the malaria parasite Plasmodium falciparum , grown in red blood cells. Of these compounds, some 13,500 inhibited parasite growth, and more than 8,000 also showed potent activity against a multidrug resistant strain. The targets of these compounds were inferred through bioinformatic analysis, revealing several new mechanisms of antimalarial action.

Key Points A chemogenomic library is a collection of well-defined pharmacological agents. A hit from such a set in a phenotypic screen suggests that the annotated target or targets of the probe molecules are involved in the phenotypic perturbation. The creation and utility of a number of chemogenomic libraries have been described, by academia and industry, and some are commercially available. Chemogenomic screening has the potential to expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications include drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities. Target identification from phenotypic screening can benefit from the integration of small-molecule chemogenomics with genetic approaches, such as RNA-mediated interference and CRISPR–Cas9. Current limitations of chemogenomic screening include small-molecule polypharmacology, misannotation of biological activity and false-positive results (deriving from compound fluorescence or luciferase reporter binding) for example, although opportunities to overcome these issues, particularly through the incorporation of computational techniques, are emerging. 'Open innovation' and collaborative ventures across academia and industry are required to create and assemble the best pharmacological probes for chemogenomic libraries. Chemogenomic screening is increasingly being applied to expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Here, Jones and Bunnage discuss the principles of the creation and use of chemogenomic libraries, highlighting key examples and their applications, including target identification, drug repositioning and predictive toxicology. The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

Botulinum toxins are neurotoxins produced by Clostridium botulinum. This toxin can be lethal for humans as a cause of botulism; however, in small doses, the same toxin is used to treat different conditions. Even if the therapeutic doses are effective and safe, the adverse reactions could be local and could unmask a subclinical impairment of neuromuscular transmissions. There are not many cases of adverse events in the literature; however, it is possible that sometimes they do not occur as they are transient and, if they do occur, there is no possibility of a cure other than to wait for the pharmacological effect to end. Inhibition of botulinum neurotoxin type A (BoNT/A) effects is a strategy for treating botulism as it can provide an effective post-exposure remedy. In this paper, 13,592,287 compounds were screened through a pharmacophore filter, a 3D-QSAR model, and a virtual screening; then, the compounds with the best affinity were selected. Molecular dynamics simulation studies on the first four compounds predicted to be the most active were conducted to verify that the poses foreseen by the docking were stable. This approach allowed us to identify compounds with a calculated inhibitory activity in the range of 316–500 nM.

Candida albicans remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals. The scarcity of antifungal agents and their limited efficacy contribute to the unacceptably high morbidity and mortality rates associated with these infections. The yeast-to-hypha transition represents the main virulence factor associated with the pathogenesis of C. albicans infections. In addition, filamentation is pivotal for robust biofilm development, which represents another major virulence factor for candidiasis and further complicates treatment. Targeting pathogenic mechanisms rather than growth represents an attractive yet clinically unexploited approach in the development of novel antifungal agents. Here, we performed large-scale phenotypic screening assays with 30,000 drug-like small-molecule compounds within ChemBridge’s DIVERSet chemical library in order to identify small-molecule inhibitors of C. albicans filamentation, and our efforts led to the identification of a novel series of bioactive compounds with a common biaryl amide core structure. The leading compound of this series, N -[3-(allyloxy)-phenyl]-4-methoxybenzamide, was able to prevent filamentation under all liquid and solid medium conditions tested, suggesting that it impacts a common core component of the cellular machinery that mediates hypha formation under different environmental conditions. In addition to filamentation, this compound also inhibited C. albicans biofilm formation. This leading compound also demonstrated in vivo activity in clinically relevant murine models of invasive and oral candidiasis. Overall, our results indicate that compounds within this series represent promising candidates for the development of novel anti-virulence approaches to combat C. albicans infections. IMPORTANCE Since fungi are eukaryotes, there is a limited number of fungus-specific targets and, as a result, the antifungal arsenal is exceedingly small. Furthermore, the efficacy of antifungal treatment is compromised by toxicity and development of resistance. As a consequence, fungal infections carry high morbidity and mortality rates, and there is an urgent but unmet need for novel antifungal agents. One appealing strategy for antifungal drug development is to target pathogenetic mechanisms associated with infection. In Candida albicans , one of the most common pathogenic fungi, morphogenetic transitions between yeast cells and filamentous hyphae represent a key virulence factor associated with the ability of fungal cells to invade tissues, cause damage, and form biofilms. Here, we describe and characterize a novel small-molecule compound capable of inhibiting C. albicans filamentation both in vitro and in vivo ; as such, this compound represents a leading candidate for the development of anti-virulence therapies against candidiasis. Since fungi are eukaryotes, there is a limited number of fungus-specific targets and, as a result, the antifungal arsenal is exceedingly small. Furthermore, the efficacy of antifungal treatment is compromised by toxicity and development of resistance. As a consequence, fungal infections carry high morbidity and mortality rates, and there is an urgent but unmet need for novel antifungal agents. One appealing strategy for antifungal drug development is to target pathogenetic mechanisms associated with infection. In Candida albicans , one of the most common pathogenic fungi, morphogenetic transitions between yeast cells and filamentous hyphae represent a key virulence factor associated with the ability of fungal cells to invade tissues, cause damage, and form biofilms. Here, we describe and characterize a novel small-molecule compound capable of inhibiting C. albicans filamentation both in vitro and in vivo ; as such, this compound represents a leading candidate for the development of anti-virulence therapies against candidiasis.

Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.

Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of >1,000 unique compounds across >500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U. S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation oí in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.

The constant emergence of new viral pathogens underscores the need for continually evolving, effective antiviral drugs. A key challenge is identifying compounds that are both efficacious and safe, as many candidates fail during development due to unforeseen toxicity. To address this, the embryonic zebrafish morphology, mortality, and behavior (ZBE) screen and the SYSTEMETRIC® Cell Health Screen (CHS) were employed to evaluate the safety of 403 compounds from the Cayman Antiviral Screening Library. Of these compounds, 114 were FDA-approved, 17 were discontinued, and 97 remained on the market. CHS identified 25% (104 compounds) as toxic, with a Cell Health Index™ (CHI) > 0.5. The embryonic zebrafish model identified an additional 20% as toxic (79), bringing the total to 183. ZBEscreen flagged 19 toxic hits among compounds still on the market, seven of which were also identified by CHS. The combined use of CHS and zebrafish models enhanced hazard detection. Together, CHS and ZBEscreen identified 45.5% of the library as potentially hazardous. Notably, the zebrafish non-hazardous compounds correlated strongly with over-the-counter or prescribed antiviral drugs, confirming their known safety profile. Over 130 hazard-associated compounds warranted further investigation. Using self-organizing maps, six distinct neighborhoods of compound similarity were identified. This dual approach streamlined the early detection of hazards associated with promising leads and is expected to facilitate faster, safer antiviral discovery.

A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory ( http://wiki.toxbank.net/toxicogenomics-map/ ) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named ‘stereotypical response.’ On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically influenced genes.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.

PurposeTo advance translational research of potential therapeutic small molecules against infectious microbes, the compounds must display a relative lack of mammalian cell cytotoxicity. Vero cell cytotoxicity (CC50) is a common initial assay for this metric. We explored the development of naïve Bayesian models that can enhance the probability of identifying non-cytotoxic compounds.MethodsVero cell cytotoxicity assays were identified in PubChem, reformatted, and curated to create a training set with 8741 unique small molecules. These data were used to develop Bayesian classifiers, which were assessed with internal cross-validation, external tests with a set of 193 compounds from our laboratory, and independent validation with an additional diverse set of 1609 unique compounds from PubChem.ResultsEvaluation with independent, external test and validation sets indicated that cytotoxicity Bayesian models constructed with the ECFP_6 descriptor were more accurate than those that used FCFP_6 fingerprints. The best cytotoxicity Bayesian model displayed predictive power in external evaluations, according to conventional and chance-corrected statistics, as well as enrichment factors.ConclusionsThe results from external tests demonstrate that our novel cytotoxicity Bayesian model displays sufficient predictive power to help guide translational research. To assist the chemical tool and drug discovery communities, our curated training set is being distributed as part of the Supplementary Material.