Drug Discovery Development Research Articles

A massively parallel reporter assay library to screen short synthetic promoters in mammalian cells

Cellular responses to stimuli underpin discoveries in drug development, synthetic biology, and general life sciences. We introduce a library comprising 6144 synthetic promoters, each shorter than 250 bp, designed as transcriptional readouts of cellular stimulus responses in massively parallel reporter assay format. This library facilitates precise detection and amplification of transcriptional activity from our promoters, enabling the systematic development of tunable reporters with dynamic ranges of 50−100 fold. Our library proved functional in numerous cell lines and responsive to a variety of stimuli, including metabolites, mitogens, toxins, and pharmaceutical agents, generating robust and scalable reporters effective in screening assays, biomarkers, and synthetic circuits attuned to endogenous cellular activities. Particularly valuable in therapeutic development, our library excels in capturing candidate reporters to signals mediated by drug targets, a feature we illustrate across nine diverse G-protein coupled receptors (GPCRs), critical targets in drug development. We detail how this tool isolates and defines discrete signaling pathways associated with specific GPCRs, elucidating their transcriptional signatures. With its ease of implementation, broad utility, publicly available data, and comprehensive documentation, our library will be beneficial in synthetic biology, cellular engineering, ligand exploration, and drug development.

Phytochemistry, Pharmacological Properties and Medicinal Uses of Apium leptophyllum: A Review

Apium leptophyllum seeds are used as an important drug in Ayurveda from ancient times. The main constituents of the seed are fats, fibre, carbohydrates and essential oils, about 50% of which consists of Thymol. Chromatographic analysis of the seed showed various essential compounds viz. Pentacosanol, β-Sitosterol, 1-nonadecanol, 8-hydroxy cuminic acid, Corosolic acid and Stigmasterol. The seeds have shown strong antioxidant properties along with various other pharmacological properties like anti-microbial, anti-fungal, anti-diabetic, anti-inflammatory, anti-diarrheal, antiasthmatic and anti-cancer properties. This review aims to provide a comprehensive overview of scientific research literature on the chemical composition and pharmacological activities of Apium leptophyllum. We are the first to report vast and updated review of this plant, as much of the work has not been done on this plant. So this review may be helpful for the researchers to explore the pharmacological properties of this plant which may lead to new discoveries in drug development.

Glycolytic Inhibition and Antidiabetic Activity on Synthesized Flavanone Scaffolds with Computer Aided Drug Designing Tools

Background: Diabetes mellitus is a challengeable metabolic disorder that leads to a group of complications when the HbA1c level is not maintained. Most of the existing drugs available in the market in long-term use may lead to serious adverse effects. Hence, current research focuses on drug development for the management of diabetes by synthesizing natural mimicking flavonoid analogues. Objective: This study focused on the synthesis of flavanone derivatives imitating natural flavonoid core and investigated for their antidiabetic and antioxidant activity, which can help in the development of drug discovery targeting diabetic management. Materials and Methods: The novel 2-phenyl-2,3-dihydro-chromen-4-ones were synthesized from 1,3-diphenyl-prop-2-en-1-one derivatives and characterized using UV, IR, 1HNMR, 13CNMR and mass spectroscopic techniques. Drug target site was determined using graph theoretical analysis and screened the characterized title compounds for their in-silico studies by analyzing their physiochemical properties, ADMET studies, and molecular docking analysis. Antidiabetic and free radical scavenging effects were investigated both by in-vitro (alpha-amylase inhibitory assay) and in-vivo models. Streptozotocin (STZ) induced rats were used as in-vivo models. Results: The α-amylase inhibitory assay showed flavanones with hydroxyl substitution HFA1- HFA7 had significant IC50 values. The test compounds (HFA3-HFA7) were investigated for their antidiabetic activity on STZ induced rats at 40 mg/kg. The blood glucose level and antioxidant enzymes were significantly restored by title compounds (HFA5, HFA4, and HFA6) with an electron-donating group such as hydroxyl, methoxy and thiophenyl group on ring B compared to glibenclamide. Conclusion: These results suggest that naturally mimicking synthesized flavanone have antidiabetic and antioxidant properties, which can aid in the development of drugs towards diabetes management.

A Sensitive Medium-Throughput Method to Predict Intestinal Absorption in Humans Using Rat Intestinal Tissue Segments

A range of in vitro, ex vivo, and in vivo approaches are currently used for drug development. Highly predictive human intestinal absorption models remain lagging behind the times because of numerous variables concerning permeability through gastrointestinal tract in humans. However, there is a clear need for a drug permeability model early in the drug development process that can balance the requirements for high throughput and effective predictive potential. The present study developed a medium throughput screening Snapwell (MTS-Snapwell) ex vivo model to provide an alternative method to classify drug permeability. Rat small intestine tissue segments were mounted in commercial Snapwell™ inserts. Unidirectional drug transport (A-B) was measured by collecting samples at different time points. Viability of intestinal tissue segments was measured by examining transepithelial electric resistance (TEER) and phenol red and caffeine transport. As a result, the apparent permeability (Papp; ×10(-6) cm/s) was determined for atenolol (10.7 ± 1.2), caffeine (17.6 ± 3.1), cimetidine (6.9 ± 0.1), metoprolol (12.6 ± 0.7), theophylline (15.3 ± 1.6) and, ranitidine (3.8 ± 0.4). All drugs were classified in high/low permeability according to Biopharmaceutics Classification System showing high correlation with human data (r = 0.89). These findings showed a high correlation with human data (r = 0.89), suggesting that this model has potential predictive capacity for paracellular and transcellular passively absorbed molecules.

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.

Natural products in modern life science.

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.

Identifying the Stable Polymorph Early in the Drug Discovery-Development Process

Identifying the Stable Polymorph Early in the Drug Discovery-Development Process