• Cyclic peptide
• IL-17B
• IL-17RB
• MLK4
• Pancreatic cancer
• Protein–protein disruptor

• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/metabolism
• Peptides, Cyclic/pharmacology
• Peptides, Cyclic/chemistry
• Animals
• Humans
• Cell Line, Tumor
• Receptors, Interleukin-17/metabolism
• Mice
• Cell Proliferation/drug effects
• Xenograft Model Antitumor Assays
• Antineoplastic Agents/pharmacology
• Protein Binding
• Mice, Nude
• Signal Transduction/drug effects

• pains
• nuisance compounds
• assay troubleshooting
• assay integrity
• assay interference
• high-through screening
• false positives

• Monash University

• Humans
• Animals
• Analgesics/pharmacology
• Analgesics/chemistry
• Signal Transduction/drug effects
• Protein Interaction Maps/drug effects
• Chronic Pain/drug therapy
• Chronic Pain/metabolism
• Pain/metabolism
• Pain/drug therapy

• COVID-19
• antivirals
• coronavirus
• covalent drugs
• dynamic light scattering
• inhibitors
• main protease
• natural products

• antiviral MOAs
• deglucuronidation-through-inflammation mechanism
• flavonoids
• inflammation
• polyphenolic antiviral mechanisms
• polyphenols

• Drug Repositioning
• SARS-CoV-2/drug effects
• Humans
• Colloids/chemistry
• Antiviral Agents/pharmacology
• Antiviral Agents/chemistry
• COVID-19 Drug Treatment
• COVID-19/virology
• Drug Evaluation, Preclinical/methods

• P50 AI150476 NIAID NIH HHS
• R35 GM122481 NIGMS NIH HHS
• T32 GM007175 NIGMS NIH HHS

This study investigated the in vitro inhibitory potential of different solvent extracts of leaves of Barbeya oleoides on key enzymes related to type 2 diabetes mellitus (α-glucosidase and α-amylase) in combination with an aggregation assay (using 0.01% Triton X-100 detergent) to assess the specificity of action. The methanol extract was the most active in inhibiting α-glucosidase and α-amylase, with IC₅₀ values of 6.67 ± 0.30 and 25.62 ± 4.12 µg/mL, respectively. However, these activities were significantly attenuated in the presence of 0.01% Triton X-100. The chemical analysis of the methanol extract was conducted utilizing a dereplication approach combing LC-ESI-MS/MS and database searching. The chemical analysis detected 27 major peaks in the negative ion mode, and 24 phenolic compounds, predominantly tannins and flavonol glycosides derivatives, were tentatively identified. Our data indicate that the enzyme inhibitory activity was probably due to aggregation-based inhibition, perhaps linked to polyphenols.

• Barbeya oleoides
• LC-ESI-MS/MS
• aggregation
• polyphenols
• type 2 diabetes mellitus
• α-amylase
• α-glucosidase

The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.

• didesmethylrocaglamide
• eIF4A inhibitors
• natural compounds
• neurofibromatosis (NF)
• protein translation
• rocaglamide
• signaling pathway
• targeted therapy

• Molecular Docking Simulation/methods
• Software
• Drug Discovery/methods

• T32 GM008284 NIGMS NIH HHS
• R01 GM133836 NIGMS NIH HHS
• R01 MH112205 NIMH NIH HHS
• R37 DA045657 NIDA NIH HHS
• T32 GM007175 NIGMS NIH HHS
• F32 GM136062 NIGMS NIH HHS
• R35 GM122481 NIGMS NIH HHS

• RNase P inhibitors
• RnpA protein subunit
• bacterial RNase P
• protein aggregators

• Benzo[d]midazole
• PAINS alert
• cytotoxicity
• quinoline
• thiophene
• tyrosine kinases

• Cystic fibrosis
• Drug repositioning
• Molecular docking
• Molecular dynamics
• Surface plasmon resonance

• aggregation
• gallotannins
• inhibition
• promiscuity
• specificity

• Thiophene
• pyran
• pyrazole
• thiazole
• triazole
• tyrosine kinase.

• Glaucoma
• Rho-Kinase inhibitors
• intraocular pressure
• neuroprotection
• ripasudil
• trabecular meshwork.

• Arylhydrazone
• cytotoxicity
• pyrazole
• thiazole
• thiophene
• tyrosine kinases

• Animals
• Antineoplastic Agents/blood
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacokinetics
• Carbamates/blood
• Carbamates/chemistry
• Carbamates/pharmacokinetics
• Colloids
• Doxorubicin/analogs & derivatives
• Doxorubicin/blood
• Doxorubicin/chemistry
• Doxorubicin/pharmacokinetics
• Drug Stability
• Excipients
• Female
• Fulvestrant/chemistry
• Humans
• MCF-7 Cells
• Mice
• Neoplasm Transplantation
• Oxazoles/blood
• Oxazoles/chemistry
• Oxazoles/pharmacokinetics
• Polysorbates/chemistry
• Prodrugs/chemistry
• Prodrugs/pharmacokinetics
• Proof of Concept Study
• Serum

• R01 GM071630 NIGMS NIH HHS
• R21 CA143549 NCI NIH HHS

The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1–RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms.

• alternative splicing
• castration-resistant prostate cancer
• computer-aided drug discovery
• hnRNP A1
• protein–RNA interactions
• small molecule inhibitors

• Animals
• Biological Products/chemistry
• Biological Products/pharmacology
• Disease
• Enzyme Activation/drug effects
• Humans
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Protein Serine-Threonine Kinases/metabolism
• Protein-Tyrosine Kinases/antagonists & inhibitors
• Protein-Tyrosine Kinases/metabolism
• Dyrk Kinases

• Anticancer
• CDK
• Hyperproliferation
• Metastatic cancer
• Mutagenesis

• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Cell Cycle/drug effects
• Cell Proliferation/drug effects
• Clinical Trials as Topic
• Cyclin-Dependent Kinases/antagonists & inhibitors
• Humans
• Molecular Structure
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/pathology
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/therapeutic use

Promiscuous inhibition due to aggregate formation has been recognized as a major concern in drug discovery campaigns. Here, we report some aggregators identified in a virtual screening (VS) protocol to search for inhibitors of human ecto-5′-nucleotidase (ecto-5′-NT/CD73), a promising target for several diseases and pathophysiological events, including cancer, inflammation and autoimmune diseases. Four compounds (A, B, C and D), selected from the ZINC-11 database, showed IC₅₀ values in the micromolar range, being at the same time computationally predicted as potential aggregators. To confirm if they inhibit human ecto-5′-NT via promiscuous mechanism, forming aggregates, enzymatic assays were done in the presence of 0.01% (v/v) Triton X-100 and an increase in the enzyme concentration by 10-fold. Under both experimental conditions, these four compounds showed a significant decrease in their inhibitory activities. To corroborate these findings, turbidimetric assays were performed, confirming that they form aggregate species. Additionally, aggregation kinetic studies were done by dynamic light scattering (DLS) for compound C. None of the identified aggregators has been previously reported in the literature. For the first time, aggregation and promiscuous inhibition issues were systematically studied and evaluated for compounds selected by VS as potential inhibitors for human ecto-5′-NT. Together, our results reinforce the importance of accounting for potential false-positive hits acting by aggregation in drug discovery campaigns to avoid misleading assay results.

• aggregation
• dynamic light scattering
• enzymatic assays
• human ecto-5′-nucleotidase
• promiscuous mechanism
• turbidimetry
• virtual screening

• Colloidal aggregates
• high-throughput screening
• protein adsorption
• self-assembly

• R01 GM071630 NIGMS NIH HHS

• Anticancer
• Docking
• Drug
• MetaPrint2D
• Self-organizing map

A significant problem in high-throughput drug screening is the disproportionate number of false hits associated with drug candidates that form colloidal aggregates. Such molecules, referred to as promiscuous inhibitors, nonspecifically inhibit multiple enzymes and are thus not useful as potential drugs. Here, we report a printable hydrogel-based drug-screening platform capable of non-ambiguously differentiating true enzyme inhibitors from promiscuous aggregating inhibitors, critical for accelerating the drug discovery process. The printed hydrogels can both immobilize as well as support the activity of entrapped enzymes against drying or treatment with a protease or chemical denaturant. Furthermore, the printed hydrogel can be applied in a high-throughput microarray-based screening platform (consistent with current practice) to rapidly ( <25 min) and inexpensively identify only clinically promising lead compounds with true inhibitory potential as well as to accurately quantify the dose–response relationships of those inhibitors, all while using 95% less sample than required for a solution assay.

False positive results significantly slow down the drug discovery process. Here, the authors developed a gel serving as a screening platform in which enzymes can be stored, stabilized, and protected from most of the compounds that typically cause these misleading results.

• Antimicrobial development
• HTS assay development
• LOPAC(1280)
• MEP pathway

• Aldose-Ketose Isomerases/antagonists & inhibitors
• Aldose-Ketose Isomerases/metabolism
• Anti-Bacterial Agents/analysis
• Anti-Bacterial Agents/pharmacology
• Enzyme Inhibitors/analysis
• Enzyme Inhibitors/pharmacology
• High-Throughput Screening Assays
• Molecular Structure
• Mycobacterium tuberculosis/drug effects
• Mycobacterium tuberculosis/enzymology
• Nucleotidyltransferases/antagonists & inhibitors
• Nucleotidyltransferases/metabolism
• Recombinant Proteins/metabolism
• Yersinia pestis/drug effects
• Yersinia pestis/enzymology

• R01 AI123433 NIAID NIH HHS

• Aggregator
• LC-MS
• MtSK
• NMR
• Non-specific inhibition
• Triton X-100

• Aniline Compounds/pharmacology
• Animals
• Aorta, Thoracic/drug effects
• Aorta, Thoracic/metabolism
• Benzamides/pharmacology
• Cells, Cultured
• Dose-Response Relationship, Drug
• Hypoxia-Inducible Factor 1/antagonists & inhibitors
• Hypoxia-Inducible Factor 1/physiology
• Mitogen-Activated Protein Kinase 1/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 1/metabolism
• Mitogen-Activated Protein Kinase 3/antagonists & inhibitors
• Mitogen-Activated Protein Kinase 3/metabolism
• Protein Kinase Inhibitors/pharmacology
• Rats
• Rats, Wistar

• MOP-102760 CIHR

Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed. Both solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.

• drug transporters
• hepatocytes
• multidrug resistance
• pharmacokinetics
• protein kinases C

The binding of four bromobenzotriazoles to the catalytic subunit of human protein kinase CK2 was assessed by two complementary methods: Microscale Thermophoresis (MST) and Isothermal Titration Calorimetry (ITC). New algorithm proposed for the global analysis of MST pseudo-titration data enabled reliable determination of binding affinities for two distinct sites, a relatively strong one with the K_d of the order of 100 nM and a substantially weaker one (K_d > 1 μM). The affinities for the strong binding site determined for the same protein-ligand systems using ITC were in most cases approximately 10-fold underestimated. The discrepancy was assigned directly to the kinetics of ligand nano-aggregates decay occurring upon injection of the concentrated ligand solution to the protein sample. The binding affinities determined in the reverse ITC experiment, in which ligands were titrated with a concentrated protein solution, agreed with the MST-derived data. Our analysis suggests that some ITC-derived K_d values, routinely reported together with PDB structures of protein-ligand complexes, may be biased due to the uncontrolled ligand (nano)-aggregation, which may occur even substantially below the solubility limit.

• Drug screening
• IDO
• Indoleamine 2,3-dioxygenase
• Inhibitors
• Molecular modeling
• Mutagenesis

• Catalytic Domain/drug effects
• Drug Discovery
• Drug Evaluation, Preclinical
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/metabolism
• Enzyme Inhibitors/pharmacology
• Humans
• Immune Tolerance/drug effects
• Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry
• Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
• Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
• Molecular Docking Simulation
• Mutation
• Structure-Activity Relationship

1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is the first committed enzyme in the 2-methyl-D-erythritol 4-phosphate (MEP) terpenoid biosynthetic pathway and is also a validated antimicrobial target. Theaflavins, which are polyphenolic compounds isolated from fermented tea, possess a wide range of pharmacological activities, especially an antibacterial effect, but little has been reported on their modes of antimicrobial action. To uncover the antibacterial mechanism of theaflavins and to seek new DXR inhibitors from natural sources, the DXR inhibitory activity of theaflavins were investigated in this study. The results show that all four theaflavin compounds could specifically suppress the activity of DXR, with theaflavin displaying the lowest effect against DXR (IC₅₀ 162.1 μM) and theaflavin-3,3′-digallate exhibiting the highest (IC₅₀ 14.9 μM). Moreover, determination of inhibition kinetics of the theaflavins demonstrates that they are non-competitive inhibitors of DXR against 1-deoxy-D-xylulose 5-phosphate (DXP) and un-competitive inhibitors with respect to NADPH. The possible interactions between DXR and the theaflavins were simulated via docking experiments.

The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify parent compounds that have the potential to be developed into effective drugs. Studies on Ebola viral proteins have shown that some can elicit an immunological response in mice, and these are now considered essential components of a vaccine designed to protect against Ebola haemorrhagic fever. The current study focuses on chemoinformatic approaches to identify virtual hits against Ebola viral proteins (VP35 and VP40), including protein binding site prediction, drug-likeness, pharmacokinetic and pharmacodynamic properties, metabolic site prediction, and molecular docking. Retrospective validation was performed using a database of non-active compounds, and early enrichment of EBOV actives at different false positive rates was calculated. Homology modelling and subsequent superimposition of binding site residues on other strains of EBOV were carried out to check residual conformations, and hence to confirm the efficacy of potential compounds. As a mechanism for artefactual inhibition of proteins through non-specific compounds, virtual hits were assessed for their aggregator potential compared with previously reported aggregators. These systematic studies have indicated that a few compounds may be effective inhibitors of EBOV replication and therefore might have the potential to be developed as anti-EBOV drugs after subsequent testing and validation in experiments in vivo.

• Ebola virus
• VP35
• VP40
• molecular docking
• phytochemicals
• retrospective validation
• virtual screening

• Reactive Blue 2
• anthraquinone
• anticancer
• drug synthesis and development
• laxative
• medicinal plants
• toxicity

Bayesian models constructed from structure-derived fingerprints have been a popular and useful method for drug discovery research when applied to bioactivity measurements that can be effectively classified as active or inactive. The results can be used to rank candidate structures according to their probability of activity, and this ranking benefits from the high degree of interpretability when structure-based fingerprints are used, making the results chemically intuitive. Besides selecting an activity threshold, building a Bayesian model is fast and requires few or no parameters or user intervention. The method also does not suffer from such acute overtraining problems as quantitative structure–activity relationships or quantitative structure–property relationships (QSAR/QSPR). This makes it an approach highly suitable for automated workflows that are independent of user expertise or prior knowledge of the training data. We now describe a new method for creating a composite group of Bayesian models to extend the method to work with multiple states, rather than just binary. Incoming activities are divided into bins, each covering a mutually exclusive range of activities. For each of these bins, a Bayesian model is created to model whether or not the compound belongs in the bin. Analyzing putative molecules using the composite model involves making a prediction for each bin and examining the relative likelihood for each assignment, for example, highest value wins. The method has been evaluated on a collection of hundreds of data sets extracted from ChEMBL v20 and validated data sets for ADME/Tox and bioactivity.

• Acoustic droplet ejection
• Assay modeling
• Bootstrap principle
• Direct dispensing
• Dispensing technologies
• Error modeling
• Liquid handling

• Acoustics/instrumentation
• Algorithms
• Animals
• Computer Simulation
• Drug Evaluation, Preclinical/instrumentation
• Enzyme Assays/instrumentation
• Equipment Design
• Humans
• Inhibitory Concentration 50
• Models, Biological
• Phosphorylation/drug effects
• Protein Kinase Inhibitors/pharmacology
• Receptor, EphB4/antagonists & inhibitors
• Receptor, EphB4/metabolism
• Uncertainty

• P30 CA008748 NCI NIH HHS