Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs.

A target-based drug discovery strategy has led to a bias away from low molecular weight (MWT) drug discovery. Analysis of the ACS chemistry registration system shows that most low MWT drugs were first made in the time era before target-based drug discovery. Therapeutic activity among most low MWT drugs was identified in the era of phenotypic drug discovery when drugs were selected based on their phenotypic effects and before screening, mechanism of action considerations and experiences with fragment screening became known.

Chloroquine Ingestion to Prevent SARS-CoV-2 Infection: A Report of Two Cases.

Introduction: Amid the global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), chloroquine and hydroxychloroquine were being studied as agents to prevent and treat coronavirus disease 2019. Information about these agents and their effects circulated throughout the general public media, raising the concern for self-directed consumption of both pharmaceutical and non-pharmaceutical products.

Case Report: We present two cases of chloroquine toxicity that occurred after ingestion of an aquarium disinfectant that contained chloroquine phosphate in a misguided attempt to prevent infection by SARS-CoV-2.

High throughput in vivo phenotypic screening for drug repurposing: Discovery of MLR-1023 a novel insulin sensitizer and novel Lyn kinase activator with clinical proof of concept.

Drug discovery requires the combination of medicinal chemistry and biology. In this article Chris Lipinski, the medicinal chemist, describes the chemical origins at Pfizer of Tolimidone the starting point for the repurposed MLR-1023 (Ochman et al., 2012).

Serum Lactate and Mortality in Emergency Department Patients with Cancer.

Introduction: Patients with malignancy represent a particular challenge for the emergency department (ED) given their higher acuity, longer ED length of stay, and higher admission rate. It is unknown if patients with malignancies and hyperlactatemia are at increased risk of mortality. If serum lactic acid could improve detection of at-risk patients with cancer, it would be useful in risk stratification.

The rule of five should not impede anti-parasitic drug development.

The "rule of 5" has become a mainstay of decision-making in the pharmaceutical industry as well as in nonindustrial (academic and institutional) drug development. However the authors of the original paper never intended for "double cutoffs" to preclude development of new drug leads for parasitic diseases.

Badapple: promiscuity patterns from noisy evidence.

Background: Bioassay data analysis continues to be an essential, routine, yet challenging task in modern drug discovery and chemical biology research. The challenge is to infer reliable knowledge from big and noisy data. Some aspects of this problem are general with solutions informed by existing and emerging data science best practices.

Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy.

Physician in Triage Versus Rotational Patient Assignment.

Background: Physician in triage and rotational patient assignment are different front-end processes that are designed to improve patient flow, but there are little or no data comparing them.

Objective: To compare physician in triage with rotational patient assignment with respect to multiple emergency department (ED) operational metrics.

Methods: Design-Retrospective cohort review.

Emergency Department Rotational Patient Assignment.

Study Objective: We compare emergency department (ED) operational metrics obtained in the first year of a rotational patient assignment system (in which patients are assigned to physicians automatically according to an algorithm) with those obtained in the last year of a traditional physician self-assignment system (in which physicians assigned themselves to patients at physician discretion).

Methods: This was a pre-post retrospective study of patients at a single ED with no financial incentives for physician productivity. Metrics of interest were length of stay; arrival-to-provider time; rates of left before being seen, left subsequent to being seen, early returns (within 72 hours), and early returns with admission; and complaint ratio.

Thermodynamic Proxies to Compensate for Biases in Drug Discovery Methods.

Purpose: We propose a framework with simple proxies to dissect the relative energy contributions responsible for standard drug discovery binding activity.

Methods: We explore a rule of thumb using hydrogen-bond donors, hydrogen-bond acceptors and rotatable bonds as relative proxies for the thermodynamic terms. We apply this methodology to several datasets (e.

Emergency department rapid medical assessment: overall effect and mechanistic considerations.

Background: Although the use of a physician and nurse team at triage has been shown to improve emergency department (ED) throughput, the mechanism(s) by which these improvements occur is less clear.

Objectives: 1) To describe the effect of a Rapid Medical Assessment (RMA) team on ED length of stay (LOS) and rate of left without being seen (LWBS); 2) To estimate the effect of RMA on different groups of patients.

Methods: For Objective 1, we compared LOS and LWBS on dates when we utilized RMA to comparable dates when we did not.

Small molecules with antiviral activity against the Ebola virus.

The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine.

Parallel worlds of public and commercial bioactive chemistry data.

The availability of structures and linked bioactivity data in databases is powerfully enabling for drug discovery and chemical biology. However, we now review some confounding issues with the divergent expansions of public and commercial sources of chemical structures. These are associated with not only expanding patent extraction but also increasingly large vendor collections amassed via different selection criteria between SciFinder from Chemical Abstracts Service (CAS) and major public sources such as PubChem, ChemSpider, UniChem, and others.

Flashback phenomenon and residual neurological deficits after the use of "bath salt" 3, 4- methylenedioxypyrovalerone.

Background: The use and abuse of designer drugs has been recognized for decades; however there are many derivatives of compounds that make their way into the community. Abuse of compound(s) known on the street as "bath salt" is on the rise.

Methods: We report the case of a 33-year-old man who complained of "flashbacks" and right arm shaking that followed a night of "bath salt" snorting.

Emergency department physician telemedical triage.

Background: Telemedical physician triage (TPT) is a potential application of telemedicine in the emergency department (ED). We report the technical success, patient satisfaction, and effect on ED throughput metrics (length of stay [LOS] and time to physician evaluation [TPE]) of TPT performed on a mobile platform.

Materials And Methods: Patients underwent standard nursing triage with or without TPT.

Safety of epinephrine for anaphylaxis in the emergency setting.

Background: While epinephrine is the recommended first-line therapy for the reversal of anaphylaxis symptoms, inappropriate use persists because of misunderstandings about proper dosing and administration or misconceptions about its safety. The objective of this review was to evaluate the safety of epinephrine for patients with anaphylaxis, including other emergent conditions, treated in emergency care settings.

Methods: A MEDLINE search using PubMed was conducted to identify articles that discuss the dosing, administration, and safety of epinephrine in the emergency setting for anaphylaxis and other conditions.

MLR-1023 is a potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo.

2(1H)-pyrimidinone,5-(3-methylphenoxy) (MLR-1023) is a candidate for the treatment of type 2 diabetes. The current studies were aimed at determining the mechanism by which MLR-1023 mediates glycemic control. In these studies, we showed that MLR-1023 reduced blood glucose levels without increasing insulin secretion in vivo.

The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes.

MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response.

Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis.

There is an urgent need for new drugs against tuberculosis which annually claims 1.7-1.8 million lives.

Olfactory and gustatory hallucinations presenting as partial status epilepticus because of glioblastoma multiforme.

Olfactory and gustatory hallucinations are not often encountered in the acute care setting but may represent the subtle presenting features of a significant underlying disease process. We describe a patient whose most striking presenting symptoms were of olfactory and gustatory hallucinations and in whom the diagnosis and treatment of a new brain tumor and partial status epilepticus occurred entirely in the emergency department. The lesion was subsequently identified as glioblastoma multiforme involving the hippocampus and amygdala.

The autophilic anti-CD20 antibody DXL625 displays enhanced potency due to lipid raft-dependent induction of apoptosis.

Despite widespread use of anti-CD20 antibodies as therapeutic agents for oncologic and autoimmune indications, precise descriptions of killing mechanisms remain incomplete. Complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity are indicated as modes of target cell depletion; however, the importance of apoptosis induction is controversial. Studies showing that the therapeutic anti-CD20 antibody rituximab (Rituxan) mediates apoptosis of tumor cell targets in vitro after cross-linking by anti-Fc reagents suggest that enhancement strategies applied to Fc-independent activities for anti-CD20 antibodies could improve therapeutic efficacy.

Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2.

The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain.

Targeting Pyk2 for therapeutic intervention.

Importance Of The Field: The focal adhesion tyrosine kinases FAK and Pyk2 are uniquely situated to act as critical mediators for the activation of signaling pathways that regulate cell migration, proliferation and survival. By coordinating adhesion and cytoskeletal dynamics with survival and growth signaling, FAK and Pyk2 represent molecular therapeutic targets in cancer as malignant cells often exhibit defects in these processes.

Areas Covered In This Review: This review examines the structure and function of the focal adhesion kinase Pyk2 and intends to provide a rationale for the employment of modulating strategies that include both catalytic and extra-catalytic approaches that have been developed in the last 3 - 5 years.