Unintentional ingestion of putative delta-8 tetrahydrocannabinol by two youth requiring critical care: a case report.

Background: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid from the cannabis plant that can be synthetically converted from cannabidiol (CBD). Most states permit the full or restricted sale of hemp and hemp-derived CBD products, and therefore, delta-8 THC products are on the rise. Delta-8 THC consumption can cause intoxication.

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit.

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition . Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor ().

Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I.

There is a shortage of compounds that are directed towards new targets apart from those targeted by the FDA approved drugs used against Mycobacterium tuberculosis. Topoisomerase I (Mttopo I) is an essential mycobacterial enzyme and a promising target in this regard. However, it suffers from a shortage of known inhibitors.

Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold.

An integrated suite of modeling tools that empower scientists in structure- and property-based drug design.

Structure- and property-based drug design is an integral part of modern drug discovery, enabling the design of compounds aimed at improving potency and selectivity. However, building molecules using desktop modeling tools can easily lead to poor designs that appear to form many favorable interactions with the protein's active site. Although a proposed molecule looks good on screen and appears to fit into the protein site X-ray crystal structure or pharmacophore model, doing so might require a high-energy small molecule conformation, which would likely be inactive.

Targeting Mycobacterium tuberculosis topoisomerase I by small-molecule inhibitors.

We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and M. tuberculosis cells.

Inhibition of Mycobacterium tuberculosis topoisomerase I by m-AMSA, a eukaryotic type II topoisomerase poison.

m-AMSA, an established inhibitor of eukaryotic type II topoisomerases, exerts its cidal effect by binding to the enzyme-DNA complex thus inhibiting the DNA religation step. The molecule and its analogues have been successfully used as chemotherapeutic agents against different forms of cancer. After virtual screening using a homology model of the Mycobacterium tuberculosis topoisomerase I, we identified m-AMSA as a high scoring hit.

Cis-amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase.

Substructural class effects surrounding replacement of a 'cis' N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents.

Design of a gene family screening library targeting G-protein coupled receptors.

An iterative process for the design of a G-protein coupled receptor (GPCR) gene family screening library has been developed. A key element of this process is the computational generation of pharmacophore descriptors of known GPCR ligands. Subsequent iterative analysis allows prioritization of scaffolds and sub-libraries for inclusion in the library.

Performance of 3D-database molecular docking studies into homology models.

The performance of docking studies into protein active sites constructed by homology model building was investigated using CDK2 and factor VIIa screening data sets. When the sequence identity between model and template near the binding site area is greater than approximately 50%, roughly 5 times more active compounds are identified than would be found randomly. This performance is comparable to docking to crystal structures.

Comparing performance of computational tools for combinatorial library design.

In using computational tools for library design it is necessary to understand the performance and limitations of available methods. This letter reports systematic comparisons of applying ligand-based and structure-based tools across therapeutic project-derived data sets. Included are assessments of performance in real-world iterative design applications and the utility of target structural information.

Informative library design as an efficient strategy to identify and optimize leads: application to cyclin-dependent kinase 2 antagonists.

The application of an informative, iterative library design strategy is presented for lead identification and optimization. The computational algorithm underlying informative design systematically uses data from both active and inactive compounds and maximizes the information gained from subsequent design-synthesis-screening cycles. Retrospective analysis of a released dataset of 17 550 compounds and corresponding cyclin-dependent kinase-2 activities showed that informative library design yields significant enrichments of active compounds and efficiently discovers novel chemotypes in comparison with commonly used diversity-similarity protocols.

Luddite: an information-theoretic library design tool.

We present an algorithm for the design of either combinatorial or discrete informative libraries. This approach is based on information theoretic techniques used extensively in coding theory. We have extended the information theoretic formalism to include an arbitrary number of property distribution constraints, such as Lipinski "drug-like" distributions.

Coupling structure-based design with combinatorial chemistry: application of active site derived pharmacophores with informative library design.

Protein structural information is combined with combinatorial library design in the following protocol. Active site maps are generated from protein structures. All possible 2-, 3- and 4-point pharmacophores are enumerated from the active site map and encoded as bit strings.

Evaluation of a novel shape-based computational filter for lead evolution: application to thrombin inhibitors.

A novel shape-feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that are ranked according to their correlation with activity. A small ensemble of these shapes and features is used to filter virtual compound libraries.