Current drug discovery technologies最新文献

Background: Swertia chirayita, Trigonella foenum-gracum and Sesamum indicum are used as traditional medicines to treat diabetes mellitus. A collection of metabolic illnesses known as diabetes mellitus (DM) involves chronic hyperglycemia caused by flaws in insulin secretion, function, or both. Innate immunity and inflammation both play important roles in the etiology of diabetes- related microvascular problems.

Objective: This study aims to examine the anti-diabetic effects and the acute toxicity of combined extract (1:1:1) of Swertia chirayita, Trigonella foenum-gracum and Sesamum indicum. To address the demand for higher effectiveness and safety, the current effort aims to construct anti-diabetic preparations containing methanolic extract from herbal medications.

Methods: The OECD 423 method was used to investigate acute toxicity in rats. Rats were used as test subjects, and rats were given a 35 mg/kg BW injection of streptozotocin to develop diabetes. The diabetic control group was given Glibenclamide 0.25 mg/kg BW, while the experimental group's diabetic rats received 125 mg/kg BW and 250 mg/kg BW of a combined methanolic extract of all plants. Among the measurements looked at were acute oral toxicity, behavioral changes, body weight, serum glucose levels, lipid profiles, oxidative stress, renal function tests, and inflammatory mediators. All the rat groups' histopathologies of the kidney, liver, and stomach were compared. The data were evaluated using analysis of variance, and a post hoc test was then carried out.

Results: The combined extracts' medium lethal doses (LD₅₀) were higher than 2000 mg/kg, indicating that they are not poisonous under the conditions that can be observed. Streptozotocin-induced diabetic rats' elevated blood glucose was found to be considerably lower (p 0.01) in the treated group of rats. In the treated group of rats, it was discovered that the damage and disarray in the cells typical of Streptozotocin-induced DM had been repaired. The treated group of rats returned to normal levels of the lipid profile, hyperglycemia, decreased serum protein and liver glycogen, increased liver function, and kidney function markers seen in the rats of the DM control group.

Conclusion: The evaluated combined methanolic extract can be considered safe for use in rats. Combining methanolic extract from all selected medicinal plants (Swertia chirayita, Trigonella foenum-gracum and Sesamum indicum) has a potential anti-diabetic effect and can be safely developed as an alternative medicine.

Background: Cancer is a worldwide issue. It has been observed that conventional therapies face many problems, such as side effects and drug resistance. Recent research reportedly used marine-derived products to treat various diseases and explored their potential in treating cancers.

Objective: This study aims to discover short-length anticancer peptides derived from pardaxin 6 through an in silico approach.

Methods: Fragmented peptides ranging from 5 to 15 amino acids were derived from the pardaxin 6 parental peptide. These peptides were further replaced with one residue and, along with the original fragmented peptides, were predicted for their SVM scores and physicochemical properties. The top 5 derivative peptides were further examined for their toxicity, hemolytic probability, peptide structures, docking models, and energy scores using various web servers. The trend of in silico analysis outputs across 5 to 15 amino acid fragments was further analyzed.

Results: Results showed that when the amino acids were increased, SVM scores of the original fragmented peptides were also increased. Designed peptides had increased SVM scores, which was aligned with previous studies where the single residue replacement transformed the non-anticancer peptide into an anticancer agent. Moreover, in vitro studies validated that the designed peptides retained or enhanced anticancer effects against different cancer cell lines. Interestingly, a decreasing trend was observed in those fragmented derivative peptides.

Conclusion: Single residue replacement in fragmented pardaxin 6 was found to produce stronger anticancer agents through in silico predictions. Through bioinformatics tools, fragmented peptides improved the efficiency of marine-derived drugs with higher efficacy and lower hemolytic effects in treating cancers.

Background: The aim of this study is to use modeling methods to estimate the antiviral activity of natural molecules extracted from Ginkgo biloba for the treatment of variola which is a zoonotic disease posing a growing threat to human survival. The recent spread of variola in nonendemic countries and the possibility of its use as a bioterrorism weapon have made it a global threat once again. Therefore, the search for new antiviral therapies with reduced side effects is necessary.

Methods: In this study, we examined the interactions between polyphenolic compounds from Ginkgo biloba, a plant known for its antiviral activity, and two enzymes involved in variola treatment, VarTMPK and HssTMPK, using molecular docking.

Results: The obtained docking scores showed that among the 152 selected polyphenolic compounds; many ligands had high inhibitory potential according to the energy affinity. By considering Lipinski's rules, we found that Liquiritin and Olivil molecules are the best candidates to be developed into drugs that inhibit VarTMPK because of their high obtained scores compared to reference ligands, and zero violations of Lipinski's rules. We also found that ginkgolic acids have good affinities with HssTMPK and acceptable physicochemical properties to be developed into drugs administered orally.

Conclusion: Based on the obtained scores and Lipinski's rules, Liquiritin, Olivil, and ginkgolic acids molecules showed interesting results for both studied enzymes, indicating the existence of promising and moderate activity of these polyphenols for the treatment of variola and for possible multi-targeting. Liquiritin has been shown to exhibit anti-inflammatory effects on various inflammation- related diseases such as skin injury, hepatic inflammatory injury, and rheumatoid arthritis. Olivil has been shown to have antioxidant activity. Olivil derivatives have also been studied for their potential use as anticancer agents. Ginkgolic acids have been shown to have antimicrobial and antifungal properties. However, ginkgolic acids are also known to cause allergic reactions in some people. Therefore, future studies should consider these results and explore the potential of these compounds as antiviral agents. Further experimental studies in-vitro and in-vivo are required to validate and scale up these findings.

In spite of the fact that many medicinal plants have been truly utilized for the management of diabetes all through the world, very few of them have been reported scientifically. Recently, a diverse variety of animal models have been established to better understand the pathophysiology of diabetes mellitus, and new medications to treat the condition have been introduced in the market. Flavonoids are naturally occurring substances that can be found in plants and various foods and may have health benefits in the treatment of neuropathic pain. Flavonoids have also been shown to have an anti-inflammatory impact that is significant to neuropathic pain, as indicated by a decrease in several pro-inflammatory mediators such TNF-, NF-B IL-6, and IL-1. Flavonoids appear to be a viable novel therapy option for macrovasular complications in preclinical models; however, human clinical data is still inadequate. Recently, several in silico, in-vitro and in-vivo aproaches were made to evaluate mechanisms associated with the pathogenesis of diabetes in a better way. Screening of natural antidiabetic agents from plant sources can be analysed by utilizing advanced in-vitro techniques and animal models. Natural compounds, mostly derived from plants, have been studied in diabetes models generated by chemical agents in the majority of research. The aim of this work was to review the available in silico, in-vitro and animal models of diabetes for screening of natural antidiabetic agents. This review contributes to the scientist's design of new methodologies for the development of novel therapeutic agents having potential antihyperglycemic activity.

Background: Nowadays, acidity is a severe problem worldwide caused by excessive gastric acid secretion by the stomach and proximal intestine.

Objective: Antacids are drugs capable of buffering stomach acid. Therefore, in our research work, we have reported the in-silico studies, synthesis, characterization, and evaluation of antacid activities of magnesium (II) complexes via the acid-base neutralization process.

Methods: In this research, some magnesium complexes were synthesized and their antacid behavior was compared with marketed products. Also, in-silico studies were performed on H+/K+ ATPase (Proton pump). All synthesized compounds were characterized by various spectroscopic techniques like UV-Vis, FT-IR, XRD, and DSC techniques.

Result: Spectroscopic analysis results showed that the semicarbazone ligand shows keto-enol isomerism and forms a coordinated stable complex with magnesium ions in the crystalline phase. The FT-IR results confirmed the presence of Mg-O stretching, N-H bending, and C=N stretching vibrations in Mg (II) complexes.

Conclusion: The antacid activities of Mg (II) complexes were excellent as compared to the semicarbazone ligand and comparable with that of marketed antacid drugs like ENO, and Pantop-D. Insilco studies also confirmed that semicarbazone ligand and its Mg (II) complexes were both found to be fitted into the active sites of molecular targets, and Mg (II) complexes showed better binding affinities towards macromolecular as compared to semicarbazone ligand.

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin-4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid-capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Introduction: Numerous clinical trials are currently investigating the potential of nitric oxide (NO) as an antiviral agent against coronaviruses, including SARS-CoV-2. Additionally, some researchers have reported positive effects of certain Sartans against SARS-CoV-2.

Method: Considering the impact of NO-Sartans on the cardiovascular system, we have compiled information on the general structure, synthesis methods, and biological studies of synthesized NOSartans. In silico evaluation of all NO-Sartans and approved sartans against three key SARS-CoV- -2 targets, namely M^pro (PDB ID: 6LU7), NSP16 (PDB ID: 6WKQ), and ACE-2 (PDB ID: 1R4L), was performed using MOE.

Results: Almost all NO-Sartans and approved sartans demonstrated promising results in inhibiting these SARS-CoV-2 targets. Compound 36 (CLC-1280) showed the best docking scores against the three evaluated targets and was further evaluated using molecular dynamics (MD) simulations.

Conclusion: Based on our in silico studies, CLC-1280 (a Valsartan dinitrate) has the potential to be considered as an inhibitor of the SARS-CoV-2 virus. However, further in vitro and in vivo evaluations are necessary for the drug development process.

Background: The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients.

Objective: The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options.

Materials and method: Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours.

Result: Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC.

Conclusion: The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.

Background: Developing more potent antibacterial agents is one of the most important tasks of scientists in the health field due to the problem of antibiotic resistance. Among the antibiotic targets, we mention MurA (UDP-N-Acetylglucosamine Enolpyruvyl Transferase), which is a key enzyme of peptidoglycan biosynthesis of the bacterial cell wall.

Objective: Our objective was to search for new inhibitors of the bacterial enzyme MurA by docking the analogues of its inhibitor T6361, a derivative of 5-sulfonoxy-anthranilic acid.

Methods: 990 analogues of T6361 were docked in the first binding site of E.coli MurA (open form) using the FlexX program, and the ADME-Toxicity profile of the best ones was evaluated by SwissADME and PreADMET web servers. .

Results: Docking results revealed two T6361 analogues to provide better energy scores than T6361, and have similar interactions with the binding site of E.coli MurA namely,3-{[2-(piperidine-1-carbonyl) phenyl]sulfamoyl}benzoic acid and 3-{[2-(pyrrolidine-1 carbonyl)phenyl]sulfamoyl}benzoic acid. Moreover, the two molecules were found to possess good pharmacokinetics and low toxicity.

Conclusion: We propose two analogues of T6361 as new potential inhibitors of MurA enzyme. Their good ADME-Toxicity profile qualifies them to reach in vitro and in vivo assays as future lead molecules.