Current drug discovery technologies最新文献

Introduction: The global burden of tuberculosis (TB) remains a major concern for society that is worsening day by day with the emergence of drug-resistant TB as well as risks associated with latent TB. Isocitrate lyase (ICL) has been shown as a potential target that plays a role in the la-tent/dormant stage of M. tuberculosis. Several inhibitors against ICL have been designed and tested, which have various side effects.

Methodology: This study focuses on the phytochemicals from plant extracts, which have anti-tuber-cular properties. A total of 1413 phytochemicals were virtually screened against ICL to identify the promising therapeutic compounds. The top four lead phytochemicals were selected based on their binding energy and subjected to redocking and intermolecular interaction analysis. These results were further validated through 100 ns MD simulation to check the stability of these complexes. The find-ings of these complexes were compared to the reference compound VGX.

Results: The top selected compound viz., Allantoin, Gallic acid, Citric acid, and 3,5-Dihydroxyben-zoic acid from virtual screening result displayed better docking score ranging from -8 kcal/mol to -7.2 kcal/mol than the reference compound VGX (-7.5 kcal/mol). Moreover, during the MD simula-tion analysis, gallic acid exhibited greater stability compared to all other compounds, including the reference compound.

Conclusion: Among selected phytochemicals, gallic acid exhibited highest stability and binding af-finity within the active site of ICL as compared to previously identified compounds, which suggests that it is as potential candidate against ICL. That can be used for further in vitro and in vivo studies to evaluate its effectiveness against TB.

Background: Capecitabine is an anticancer antimetabolite of fluorouracil that inhibits cell proliferation and impairs DNA repair in cancer cells. It is given specifically to treat metastatic breast, gastric and colorectal cancers.

Objective: To design, formulate, optimize and evaluate Capecitabine Nanosuspension using the QbD Box-Behnken model.

Methods: Deploying the Box-Behnken Design (BBD) model, Capecitabine nanosuspension was for-mulated with seventeen runs; the independent variables selected are Pullulan concentration, Poloxamer F407 concentration, and sonication time. The developed nanosuspension was evaluated for particle size, Zeta potential, entrapment efficiency, in vitro drug release, and anti-cancer effectiveness. Drug-excipient compatibility was assessed using the Fourier transform infrared spectroscopy method. X-ray Diffraction studies and Differential Scanning Calorimetry were used to perform and assess the crys-talline nature. Additionally, characteristics of the developed nanosuspension were assessed by per-forming a scanning electron microscopy study.

Results: The effect of various factors on key responses, namely particle size, entrapment efficiency, and drug release up to 8 hours, was assessed. A polynomial equation was employed through the anal-ysis to optimize the formulation, considering the significance levels indicated by the p-values. Notably, these variables demonstrated a substantial influence on the responses. The comparison between ob-served and predicted values revealed a relatively minor variance (85.90, 69.57, and 76.34 for particle size, entrapment efficiency, and percentage drug release at 8 hours, respectively), indicating the mod-el's suitability. The prepared nanosuspension exhibited compatibility with the used excipients, with capecitabine-entrapped nanoparticles uniformly dispersed within the suspending medium.

Conclusion: Developed capecitabine nanosuspension demonstrated better efficacy and effectiveness against gastric cancer, with independent variables like pullulan and Poloxamer F207 concentration, along with sonication time, influencing particle size, entrapment efficiency, and drug release.

Alginate, a naturally occurring polysaccharide, exhibits immense potential for diverse ap-plications due to its ability to undergo chemical modifications and blend with other constituents. These modifications enable the creation of alginate derivatives that are not only biocompatible for biomedical and tissue engineering applications but also crucial for the thriving field of bioelectronics. Alginate derivatives serve multiple functions, including their use in wound dressings, scaffolds for drug delivery and tissue engineering, as well as key components in hydrogel formulations. Recent studies highlight the immunomodulatory properties of alginate and its derivatives, including porphy-rans, fucoidan, and chitin. These materials enhance the innate immune system, rebalance the Th1/Th2 ratio towards Th1, reduce IgE synthesis, and inhibit mast cell degranulation, alleviating allergic symptoms. In pharmaceuticals, alginate-based materials are utilised as substitutes and bio-linkers in 3D bioprinting, demonstrating their potential for creating complex tissue constructs. This review un-derscores the fundamental characteristics of alginates, outlines various chemical modification meth-odologies, and discusses recent developments in the fabrication of functional alginate-based compo-sites. By presenting this synthesis of relevant information, we aim to inspire further scientific break-throughs in the development of biocompatible electronic devices and intelligent materials.

Background: The search for potent anticancer agents has accelerated the evaluation of a wide variety of pharmacological scaffolds, including oxazole derivatives. Although they are currently underexplored, they are promising as anticancer agents. This research covers the synthesis and structure-activity relationships of oxazole-based compounds.

Methods: The authors designed and synthesized new oxazole derivatives and screened them for their anticancer activity using both computational and experimental methods. Molecular docking studies were performed to identify possible targets based on literature and the interaction of these molecules with anticancer targets like c-Kit tyrosine kinase (TRK) and MDM2. The compounds were tested using the MTT assay on a panel of different cancer cell lines, including MCF-7, to evaluate their potential effectiveness.

Results: Optimized and robust synthetic procedures were developed for oxazole-based Schiff bases, with their structures confirmed through spectral analyses. Compounds 4a-e exhibited significantly stronger anticancer activity, suggesting some Structure-Activity Relationship (SAR) nuances within the series. The biological activities (IC₅₀) were determined to be in the range of 80-100 μg/mL, while molecular docking indicated that compound 4c could serve as a potential lead for c-Kit Tyrosine Kinase (TRK) inhibition.

Conclusion: The results obtained from the present study corroborate the hypothesis that oxazole derivatives are potent anticancer agents, consistent with predictions from molecular docking studies. These findings highlight the significance of the oxazole scaffold in anticancer drug discovery and encourage further exploration of structure-activity relationships to enhance therapeutic potential. Although compound 4c showed better interactions in docking studies compared to biological screening, this suggests that pharmacokinetic issues should be addressed. Future studies are likely to include in vivo models and detailed mechanistic evaluations to validate these findings and support the development of oxazole-derived anticancer compounds.

Objective: This manuscript, aimed to prepare a scientific report, underscores the pharma-cotherapeutic aspects, including therapeutic indications, mechanisms of therapeutic action, pharma-cokinetics, adverse reactions, safety in special cases, approximate costs, etc., of USFDA-approved novel drugs in the year 2023 and serve as a treasured resource for academia, researchers, patients, and clinicians.

Methods: This comprehensive report was prepared by reviewing the pre-clinical and clinical data of the USFDA-approved novel drugs available in the public domain, especially on the website of the USFDA, National Library of Medicine, Clinical Trials, other online resources, and cross-references.

Results: The USFDA has approved 55 novel drug therapies in the year 2023 and identified 38 drugs as new chemical entities (29 small molecules, 5 peptides, and 4 oligonucleotides) and 17 new biologics. About 51% (28 out of 55) of drugs were recommended for rare diseases and designated as orphan drugs. In addition to the therapeutic aspects and general description, the approximate cost or price and safety studies in special cases such as lactating and pregnant women, pediatrics, and geriatrics of all novel drug therapies are meticulously presented in the manuscript.

Conclusion: The novel drug therapies approved by the USFDA hold significant potential to enhance the patient's care by providing advanced treatment modalities. This manuscript, reporting the comprehensive description of therapeutic aspects of the mentioned new drug therapies, underscores the commitment of the pharmaceutical sector to address the unmet medical needs and reshape the landscape of the healthcare service system by instilling optimism among patients and healthcare providers.

Chromothripsis, a phenomenon of massive genomic rearrangements, introduces extensive mutations in critical genes, affecting cell survival and apoptosis. Among these genes, the BCL2 (B-cell lymphoma 2) gene, which plays a crucial antiapoptotic role in cancer cells, is often subjected to significant alterations. Here, we present a computational pipeline to model and analyze the structural and functional impacts of chromothripsis-induced Single-Nucleotide Polymorphisms (SNPs) within the BCL2 gene. This pipeline integrates mutation simulation, homology modeling, and protein inter-action analysis to evaluate the stability and apoptotic potential of BCL2 mutations. These results indicate that chromothripsis-induced mutations can destabilize the Bcl-2 protein, thereby disrupting its binding affinity with apoptotic regulators, such as Bax. These findings support the potential of ergodic anticancer therapy to exploit such mutations, facilitating the apoptosis of cancer cells. Our computational model offers a novel in silico approach for understanding mutation-driven alterations in cancer biology, aiding the development of therapeutic strategies targeting apoptotic pathways.

Diabetes mellitus (DM) is a prevalent metabolic disorder with a rapidly rising global inci-dence, presenting a significant burden to healthcare systems worldwide. Flavonoids, a class of natu-rally occurring polyphenolic compounds, are well-documented for their diverse pharmacological ac-tivities, particularly their anti-diabetic and anti-inflammatory effects. These secondary metabolites are commonly found in fruits, vegetables, and fungi and are classified into six main subclasses: fla-vanols, flavones, flavanones, isoflavones, anthocyanidins, and chalcones. The interplay between hy-perglycemia, inflammation, and vascular complications in diabetes is now well recognized. Flavo-noids with anti-diabetic properties may help mitigate inflammation by reducing hyperglycemia through various mechanisms. This review explores the antidiabetic potential and molecular mecha-nisms of citrus flavonoids, drawing on updated evidence from in vitro and in vivo studies. Flavonoids are shown to regulate biomarkers of glycemic control, lipid metabolism, renal function, hepatic en-zymes, and antioxidant defenses. They also modulate signaling pathways implicated in glucose up-take and insulin sensitivity, which are central to the development of diabetes and its complications. Furthermore, this review synthesizes current knowledge on the antidiabetic effects of dietary flavo-noids, emphasizing their molecular mechanisms in modulating key pathways such as glucose trans-porters, hepatic enzymes, tyrosine kinase inhibitors, AMP-activated protein kinase (AMPK), peroxi-some proliferator-activated receptors (PPARs), and nuclear factor kappa B (NF-κβ). Further research is essential to deepen our understanding of flavonoids' therapeutic mechanisms in managing diabetes.

Habitual inflammation is defined as the persistent activation of the body's susceptible sys-tem in response to harmful events. This ongoing inflammatory process can sometimes harm normal organs & tissues. Crucially, chronic inflammation has been linked to the emergence and advancement of a variety of disorders, including cardiovascular diseases, respiratory issues, metabolic illnesses, neurological disorders, and cancer. These diseases are classified as chronic-degenerative conditions due to the sustained and persistent nature of the underlying chronic inflammatory processes. Treating patient's inflammation creates new therapeutic opportunities for these related illnesses. In this review, we will study the role of inflammation during the onset of rheumatoid arthritis. Further-more, we will explore diseases associated with chronic inflammation. Rheumatoid Arthritis (RA) is a persistent autoimmune condition causing joint inflammation. It commonly affects joints of hands, wrists, fingers, elbows, shoulders, neck, back, hips, knees, ankles, and toes. We will discuss various herbal drug therapies that help in treating and providing relief from joint pain in rheumatoid arthritis. Herbal medicines are preferable since they are safer and have fewer adverse effects than the synthetic ones. However, they are not completely safe, and therefore, toxicity studies are being conducted. . Herbal medications' phytochemicals are generally beneficial in the treatment of infectious, autoim-mune, and seditious disorders; they are especially helpful in the management of arthritis. Arthritis is one of the leading causes of impairment in the quality of life for millions of people globally. The purpose of this review is to explore the role of inflammation in rheumatoid arthritis and its association with chronic inflammation. This article highlights the importance of herbal medicine as one of the treatment options for rheumatoid arthritis.

Microgravity, space radiation, and pharmaceutical degradation are all long-term chal-lenges for astronauts traveling through space. Radiation exposure is one of the greatest health risks to astronauts in space. Associated with these conditions are acute radiation syndromes, degenerative tissue effects, damage to the central nervous system (CNS), and carcinogenesis. Microgravity and the stress people experience as astronauts cause immunological dysregulation. This study explores strat-egies to counteract the problems of microgravity and its related health risks, including protection against space radiation, prevention of pharmaceutical degradation, and advancements in the emerging field of astropharmacy.

Background: Biofilm formation by microorganisms, specifically bacteria, threatens vari-ous fields, including biomedicine and the environment. The development of biofilms has associations with increased resistance to antimicrobial agents and immune responses; it poses a significant threat to human health. ESKAPE pathogens, a group of bacteria known for their multidrug resistance, are particularly adept at biofilm formation. This research explores strategies to combat biofilm-associated infections, with a focus on natural compounds as potential anti-biofilm agents.

Methods: The study investigates 23 natural compounds for their druglike properties in fighting against antibiotic-resistant biofilms. These compounds include flavonoids, terpenes, and alkaloids, and exhibit promising bioavailability and usage potential as ligands. Molecular docking analysis em-ploying AutoDock Vina was used to evaluate the binding affinities of these ligands to key biofilm-forming genes and membrane proteins in ESKAPE pathogens.

Results: Despite a few violations of a variety of established criteria, the overall safety and efficiency of oral drug reception are maintained, emphasizing their potential for further drug development. The results show specific ligands, such as Baicalin, Apigenin, Azadirachtin, Curcumin, Hyperforin, etc., demonstrating high binding energies against biofilm-associated proteins. This approach aligns with the pursuit of sustainable alternatives to combat biofilm-related infections.

Conclusion: Natural compounds like Baicalin, Apigenin, Azadirachtin, Curcumin, Hyperforin not only exhibit broad-spectrum coverage but also show reduced risks of resistance development com-pared to synthetic antibiotics. The integration of natural compounds into multifaceted strategies con-siders the complexities of the biofilm matrix, bacterial diversity, and pathogen characteristics, offer-ing a sustainable approach to address biofilm-associated infections.