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The discovery of the interactome of cannabidiol (CBD), a non-psychoactive cannabinoid from Cannabis sativa L., has been here performed on chronic myelogenous leukemia cancer cells, using an optimized chemo-proteomic stage, which links Drug Affinity Responsive Target Stability with Limited Proteolysis Multiple Reaction Monitoring approaches. The obtained results showed the ability of CBD to target simultaneously some potential protein partners, corroborating its well-known poly-pharmacology activity. In human chronic myelogenous leukemia K562 cancer cells, the most fascinating protein partner was identified as the 116 kDa U5 small nuclear ribonucleoprotein element called EFTUD2, which fits with the spliceosome complex. The binding mode of this oncogenic protein with CBD was clarified using mass spectrometry-based and in silico analysis.

Through a comprehensive molecular docking study, a unique series of naphthoquinones clubbed azetidinone scaffolds was arrived with promising binding affinity to Mycobacterial Cytbc1 complex, a drug target chosen to kill multi-drug resistant Mycobacterium tuberculosis (MDR-Mtb). Five compounds from series-2, 2a, 2c, 2g, 2h , and 2j, showcased significant in vitro anti-tubercular activities against Mtb H 37 Rv and MDR clinical isolates. Further, synergistic studies of these compounds in combination with INH and RIF revealed a potent bactericidal effect of compound 2a at concentration of 0.39 μg/mL, and remaining (2c, 2g, 2h , and 2j) at 0.78 μg/mL. Exploration into the mechanism study through chemo-stress assay and proteome profiling uncovered the down-regulation of key proteins of electron-transport chain and Cytbc1 inhibition pathway. Metabolomics corroborated these proteome findings, and heightened further understanding of the underlying mechanism. Notably, in vitro and in vivo animal toxicity studies demonstrated minimal toxicity, thus underscoring the potential of these compounds as promising anti-TB agents in combination with RIF and INH. These active compounds adhered to Lipinski's Rule of Five, indicating the suitability of these compounds for drug development. Particular significance of molecules NQ02, 2a , and 2h , which have been patented (Published 202141033473). [Display omitted] • Naphthoquinones-azetidinone hybrids displayed potent anti-TB activity against H37Rv and MDR strains of Mtb. • Compound 2a showed remarkable bactericidal effect in combination with INH and RIF. • Proteomics and metabolomics studies revealed down-regulation of key proteins associated with cytbc1 complex inhibition. • The compound 2a showed minimal in vitro and in vivo toxicities, and suggests for future studies. [ABSTRACT FROM AUTHOR]

Drug development in oncology is highly challenging, with less than 5% success rate in clinical trials. This alarming figure points out the need to study in more details the multiple biological effects of drugs in specific contexts. Indeed, the comprehensive assessment of drug poly-pharmacology can provide insights into their therapeutic and adverse effects, to optimize their utilization and maximize the success rate of clinical trials. Recent technological advances have made possible in-depth investigation of drug poly-pharmacology. This review first highlights high-throughput methodologies that have been used to unveil new mechanisms of action of existing drugs. Then, we discuss how emerging chemo-proteomics strategies allow effectively dissecting the poly-pharmacology of drugs in an unsupervised manner. • Poor target validation and lack of biomarkers lead to high rate of drug attrition. • Compound-centric and functional genomic screens can identify cancer vulnerabilities. • Chemo-proteomics can unveil the poly-pharmacology of drugs. [ABSTRACT FROM AUTHOR]

Ancient civilizations used natural products as food and as resources to treat various diseases. Today, food ingredients, especially those derived from plants, still play important roles in human nutrition and drug discovery. The health-promoting bioactive compounds or drug candidates need to be identified systematically and efficiently, for developing healthy diets and for alleviating the burden of chronic diseases worldwide. In this multi-disciplinary process, the separation and identification of diverse molecules, the analysis of their interactions with cellular targets, the chemical synthesis, and the animal and clinical trials, are all equally important. The focus of this mini-review is on the initial stage of the process, which is critical to future trends of health foods and food-derived drug discoveries. Through the strategy of targeting the critical proteins involved in many chronic diseases, the bioactive components can be fished out and studied further. Three of the major methodologies to accelerate the discovery of the bioactive components: high throughput screening, phage display technique and virtual screening, are summarized with successful examples. The efficient strategy to identify and further validate the cellular targets, the in silico target prediction and the mass spectroscopy-based proteomics, are also highlighted. To achieve this very promising research goals, through the strategy of targeting the critical proteins involved in many chronic diseases, the establishment of an International Food Ingredients Consortium (IFIC) is proposed. • Chronic diseases may be prevented by nutritional interventions. • Drug discovery via high throughput screening, phage display, and virtual screening. • Cellular target identification by in silicon prediction and chemo-proteomics. • The needs to establish IFIC (International Food Ingredients Consortium). [ABSTRACT FROM AUTHOR]

The discovery of the interactome of cannabidiol (CBD), a non-psychoactive cannabinoid from Cannabis sativa L., has been here performed on chronic myelogenous leukemia cancer cells, using an optimized chemo-proteomic stage, which links Drug Affinity Responsive Target Stability with Limited Proteolysis Multiple Reaction Monitoring approaches. The obtained results showed the ability of CBD to target simultaneously some potential protein partners, corroborating its well-known poly-pharmacology activity. In human chronic myelogenous leukemia K562 cancer cells, the most fascinating protein partner was identified as the 116 kDa U5 small nuclear ribonucleoprotein element called EFTUD2, which fits with the spliceosome complex. The binding mode of this oncogenic protein with CBD was clarified using mass spectrometry-based and in silico analysis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)