Allosteric modulators targeting GPCRs

López-Rodrı́guez, Marı́a L.; Benhamú, Bellinda; Vázquez-Villa, Henar

doi:10.1016/b978-0-12-816228-6.00011-8

Cited by 5 publications

(5 citation statements)

References 314 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The capacity of the new NPM1 inhibitor to trigger stem cell apoptosis has been translated to ex vivo and in vivo efficacy in models of acute myeloid leukemia (AML). 19 Our results support phenotypic drug discovery as a valuable approach to develop active molecules in a pathologically relevant model, which together with the validation of the target protein involved in the disease, contributes to enhance innovation and deliver truly novel therapeutics for unmet medical needs. 20 , 21 …”

Section: Introductionsupporting

confidence: 63%

Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia

Algar,

Vázquez-Villa,

Aguilar-Garrido

et al. 2024

JACS Au

Self Cite

View full text Add to dashboard Cite

The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.

show abstract

Section: Introductionsupporting

confidence: 63%

Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia

Algar,

Vázquez-Villa,

Aguilar-Garrido

et al. 2024

JACS Au

Self Cite

View full text Add to dashboard Cite

show abstract

“…Allosteric ligands have been studied in the last 20 years because they present better receptor selectivity and potency than orthosteric ligands due to allosteric positions are less preserved across proteins and the opposition with endogenous is eliminated [51][52][53]. Allosteric modulators can be positive allosteric modulators (PAM) or NAM [54].…”

Section: -Si)mentioning

confidence: 99%

Decoding the Molecular Dance: In Silico Exploration of Cannabinoid Interactions with Key Protein Targets for Therapeutic Insights

Docampo-Palcios,

Ramirez,

Tesfatsion

et al. 2024

Preprint

View full text Add to dashboard Cite

As hemp-based cannabinoids are continuously gaining popularity, synthesis and extraction methods for these compounds are ever-changing. Within the cannabinoid market, hydrogenated derivatives are also gaining popularity at an accelerated rate, with the need for in-depth analysis of these compounds pertinent to increasing the knowledge of cannabis chemistry. Our lab used Schrödinger to dock natural and synthetic cannabinoids in various CB1 and CB2 receptors, PPAR-γ, PAK1, and GPR119 complex including several enzymes, to evaluate the interacting residues within the known binding pockets, comprising the computation of binding energies, predicting ADME characteristics, and evaluating P450 sites of metabolism. The purpose of identifying active residues, sites of metabolism, and ADME characteristics for 40 various cannabinoids is to provide guidance in computer-aided drug design and rationalization in designing and synthesis of analogs.

show abstract

“…Allosteric ligands have been studied in the last 20 years because they present better receptor selectivity and potency than orthosteric ligands due to allosteric positions are less preserved across proteins and the opposition with endogenous is eliminated [39][40][41]. Allosteric modulators can be positive allosteric modulators (PAM) or NAM [42].…”

Section: Cb1 (5u09 6kqi 7v3z) and Cb2 (5zty 6kpc 6pt0)mentioning

confidence: 99%

In Silico ADME, binding affinities, and properties of synthetic and natural cannabinoid analogs

Docampo-Palcios,

Ramirez,

Tesfatsion

et al. 2023

Preprint

View full text Add to dashboard Cite

In recent years, a new set of compounds identified as semi-synthetic cannabinoids have arisen in the market as an alternative to prohibited marijuana or its major natural cannabinoids. These compounds, which are active on the same G protein-coupled receptors (GPCRs) as cannabinoids persist to gain acceptance due to the same cannabinoid-like effects they generate. A dataset of 44 semi-synthetic and natural cannabinoids and their diastereomers were docked using Schrodinger computational software, demonstrating their binding interactions within known binding pockets and domains, predicting their ADME characteristics, p450 estimated sites of metabolism, and hypothesized metabolites.

show abstract

Allosteric modulators targeting GPCRs

Cited by 5 publications

References 314 publications

Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia

Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia

Decoding the Molecular Dance: In Silico Exploration of Cannabinoid Interactions with Key Protein Targets for Therapeutic Insights

In Silico ADME, binding affinities, and properties of synthetic and natural cannabinoid analogs

Contact Info

Product

Resources

About