Current drug discovery technologies最新文献

Background: The quantitative structure-property relationship (QSPR) modelling can be helpful in the in-silico prediction and pre-determination of the drug permeability values of a large number of compounds through human intestinal enterocytes for screening of potential candidate drugs, thereby enhancing oral drug development.

Methods: The present study involved the development of a regression-based QSPR model for the prediction of Caco-2 cell-permeability values of compounds. The training of the model was carried out on a novel large dataset of 1272 compounds with 30 selected 2D descriptors.

Results: An R2 value of 0.96 suggested that the model was significant. Finally, the model was applied in the virtual screening of 49,430 potential compounds of the CAS database of antiviral compounds, among which the model successfully screened 100 compounds as potential leads, with 96 compounds falling within the Applicability Domain (AD).

Conclusion: The present study highlights in-silico screening, which could be beneficial for the early stages of drug development.

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: 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.

Background: Type II diabetes mellitus is treated as one of the detrimental diseases and the drugs used for its treatment often lead to several side effects. Therefore, herbal medication of plant origin with lesser offshoot is a significant concern. Petroselinum crispum is a plant of pharma-ceutical interest. The present work aims to explore the potentiality assessment of flavonoids of Pe-troselinum crispum as an α-amylase inhibitor.

Methods: Compounds were extracted from the database and evaluated through drug likeliness prop-erties, ADMET and toxicity assessment. Molecular docking was done to identify the best ligand, and the dynamics simulation study was performed with the leading ligand-protein complex.

Results: Amongst the 15 bioactive compounds, apigenin appeared as the best ligand among all the studied compounds. Moreover, drug likeliness, physiochemical characteristics, and ADMET anal-yses revealed that apigenin does not deviate from Lipiniski's rule of five. Non-toxic apigenin showed a satisfactory docking score of -9.5 kcal/mol with human pancreatic α-amylase compared to the ref-erence molecule acarbose. Apigenin- α-amylase complex and apoprotein were subjected to 100ns molecular dynamics simulation to analyze the stability of the docked protein-ligand complex. The values of RMSD, RMSF, Rg, SASA and hydrogen bonding of the screened complexes showed high stability and less fluctuations of the apigenin- α-amylase complex.

Conclusion: This finding suggests apigenin as alternative therapeutics in treating diabetes mellitus by targeting the enzyme α-amylase which can be used for in vitro cross-validation studies. This study is the first documentation of the antidiabetic potentiality of the flavonoid compounds of Petroselinum crispum through in silico investigation.

The temperate, subtropical climates of Odisha state, India, provide significant benefits that can help it become a potent producer of many species of edible mushrooms. The importance of mush-rooms in diets has gained more attention in recent years due to their nutritional benefits. We aimed to update and discuss the current research information on nutritional components, including carbo-hydrates (β-glucans, trehalose, glucose), dietary fiber, proteins (ostreatin), amino acids (valine, glu-tamine, glutamic acid, aspartic acid, and arginine, lipids, vitamins (thiamine, riboflavin, pyridoxine, pantothenic acid, niacin, folic acid, nicotinic acid, and cobalamin), minerals (K, P, Na, Ca, Mg), flavor and taste contents of Odisha cultivated edible mushrooms. Additionally, their biological appli-cation in terms of antimicrobial action, antitumor, anti-inflammatory, anti-diabetic, cardioprotective properties, and antioxidant properties with mechanism of action are highlighted. Besides, we men-tioned the limitations and prospects of mushrooms.

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An imbalance between Reactive Oxygen Species (ROS) and antioxidants in the circulatory system leads to oxidative stress, which has been linked to several pathological conditions, including cancer, aging, and neurological and cardiovascular diseases. Antioxidants play a crucial role in re-ducing oxidative damage by neutralizing harmful free radicals and preventing cellular injury. The processes generating cellular oxidative stress and the curative effects of antioxidants, the origins and effects of reactive oxygen species (ROS), the role that oxidative stress plays in the pathogenesis of disease, and the several kinds of antioxidants-including enzymatic and non-enzymatic antioxidants are thoroughly explored in this review. We also emphasized the medicinal uses of antioxidants, both natural and synthetic, in the prevention and treatment of disorders associated with oxidative stress. Furthermore, we discussed the challenges and potential paths ahead for antioxidant research, such as developing new antioxidant molecules with higher efficacy and improving antioxidant delivery sys-tems. This study provides information regarding the complicated dynamics of oxidative stress and the potential benefits of antioxidants for preserving cellular homeostasis and advancing human health.

Non-coding RNA (ncRNA) has been recognized to be an essential regulator of cellular processes and gene expression in cancer. The present study covers the various roles of ncRNAs, including circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miR-NAs), that affect cancer properties. Oncogenesis, metastasis, and treatment resistance are all pro-cesses involving ncRNAs, which have tremendous potential as new therapeutic agents and tar-gets. The review covers the broad spectrum of ncRNAs in cancer biology, including their types and activities, epigenetic control, function in metastasis and angiogenesis, detection and profiling ap-proaches, potential as biomarkers, and therapeutic possibilities. Recent advancements in next-gener-ation sequencing and other molecular methods have helped us better understand how ncRNAs work and their potential therapeutic uses. However, there are still challenges to standardizing detection technologies and producing effective RNA-based therapeutics. Therefore, further studies are needed to solve important issues in this sector. Standardization efforts are also essential to developing iden-tical methods for ncRNA collection, quantification, and analysis throughout multiple laboratories and ensuring the findings are reliable and comparable. Large-scale, multi-recentre studies are required to verify the diagnostic usefulness of ncRNA biomarkers across a wide range of patient groups. Also, more detailed mechanistic knowledge is necessary for understanding the particular molecular mech-anisms by which ncRNAs affect cancer growth, metastasis, and treatment response. This review high-lights the complex relationships between ncRNAs and cancer biology and also focuses on their po-tential effect on cancer diagnosis and treatment. It also highlights the necessity for more studies to fully understand the therapeutic potential of ncRNAs in cancer. As studies advance, using ncRNA results in clinical practice might change cancer treatment by novel opportunities for specific therapy and personalized medicine.

Objective: This study investigated the antimicrobial properties of the thanatin peptide against oral bacteria associated with dental caries and endodontic failures. Additionally, the cytotoxic effects of this peptide on human gingival fibroblast cells (HGFCs) were assessed.

Methods and materials: The antimicrobial property of thanatin was tested on Streptococcus mutans, Streptococcus salivarius, Streptococcus oralis, and Enterococcus faecalis, using the microbroth dilu-tion method. The 0.2% Chlorhexidine mouthwash was used as the control group. Additionally, the cytotoxicity was measured using the MTT assay. The results were presented descriptively and ana-lyzed via one-way ANOVA and Tukey's HSD tests.

Results: Thanatin demonstrated the strongest bacteriostatic effect (MIC) against S. salivarius, meas-uring 4.68 μg/ml, which is approximately double that of S. mutans and S. oralis, with concentrations of 9.37 and 8.75 μg/ml, respectively. The highest bactericidal activity (MBC) of thanatin was noted in S. salivarius and S. oralis at 9.37 μg/ml. The antibacterial effects of thanatin against evaluated bacteria were several times lower than those of Chlorhexidine. The cytotoxicity assessment indicated that over 70% and 60% of the HGFCs remained viable after 24 and 48 hours, respectively.

Conclusion: Although thanatin exhibited significantly higher biocompatibility, its antimicrobial ef-fectiveness against the tested oral bacteria was inferior to that of 0.2% Chlorhexidine.

Introduction: Antimicrobial resistance (AMR), according to the World Health Organi-zation, is one of the most serious risks to global public health and development. It is a serious health hazard, with over 10 million deaths expected by 2050. New treatment materials and ways to remove AMR pathogens are in great demand to combat illnesses caused by such bacteria. Hence, the current work focused on virtual screening of the therapeutic potential of new oxindole derivatives against the targeted enzymes for antibacterial activity.

Materials and methods: A series of 120 novel 3-substituted-2-oxindole derivatives were designed based on the literature and SAR study, which were screened for their binding affinity against tar-geted enzymes, such as methionyl-tRNA synthetase (1PFV) and tyrosyl-tRNA synthetase (1JIL) using AutoDock Vina software. Compounds with significant binding energy were identified and filtered for appropriate ADME properties using the SwissADME program. Furthermore, the top fifteen hit compounds were evaluated for toxicity risk and drug score with the pkCSM online tool and OSIRIS Property Explorer, respectively.

Results and discussion: The docking analysis of the top two hits revealed that compounds 4 and 6 had a binding affinity of -10.1 Kcal/mol and -10.0 Kcal/mol against the targeted enzymes, respec-tively, compared to the standard (Tetracycline -9.3 Kcal/mol and Mupirocin -7.5 Kcal/mol).

Conclusion: Hence, the best-hit compound 4 underwent MD simulation, validating its stability and successfully satisfying all in silico parameters, necessitating further synthesis and screening for in-vitro antimicrobial activity. These novel oxindole scaffolds could thus serve as promising leads for effective antibacterial drugs.