Potential Drug Research Articles

Potential drugs in COVID-19 management.

The SARS-CoV-2 virus first emerged in China in December 2019 and quickly spread worldwide. Despite the absence of a vaccination or authorized drug specifically developed to combat this infection, certain medications recommended for other diseases have shown potential effectiveness in treating COVID-19, although without definitive confirmation. This review aims to evaluate the existing literature on the efficacy of these medications against COVID-19. The review encompasses various potential treatments, including antiviral medications, anti-malaria and anti-rheumatic drugs, vaccines, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), antipyretic and analgesic medicines, antiparasitic drugs, and statins. The analysis also addresses the potential benefits and drawbacks of these medications, as well as their effects on hypertension and diabetes. Although these therapies hold promise against COVID-19, further research, including suitable product production or clinical testing, is needed to establish their therapeutic efficacy.

Design and Synthesis of Gefitinib Derivatives as Potential Drugs fo r Cancer Treatment: Antiproliferative Activity, Molecular Docking, and ADMET Prediction

Background: Non-small cell lung cancer is one of the most common cancers worldwide, and targeted chemotherapy has become a kind of the main treatment. Gefitinib, the most widely studied targeted agent in non-small cell lung cancer, is an orally active tyrosine kinase inhibitor. However, gefitinib inevitably generates acquired drug resistance, leading to treatment failure. Objective: A new class of compounds containing 4-anilinoquinazoline lead structure was designed and synthesized by modifying the structure of gefitinib. These compounds are expected to exert better anticancer activity and better binding to the EGFR-TK domain, enrich the structure of 4-anilinoquinazoline derivatives and inspire further structural modifications. Methods: The antiproliferative activity of nine derivatives was determined in three cancer cell lines (A549, PC9, and HepG2) using the MTT method. The ADMET profile of all compounds was predicted, and the binding affinity of the compounds (5 and 6) to EGFR was predicted by Schrödinger. In addition, the effect of these compounds (3-6) in inducing apoptosis in HepG2 cells was also studied. Results: Four (3, 5, 6 and 9) of the newly synthesized derivatives exhibited superior antiproliferative activity against A549 to gefitinib (IC50 = 12.64 ± 3.59 μM), with compound 5 having the best activity (IC50 = 7.39 ± 1.24 μM). Moreover, the ability of compounds (3-6) to induce HepG2 cell apoptosis was significantly better than that of gefitinib. Conclusion: Nine structures (compounds 2-10) were synthesized and characterized, and compound 5 had the best antiproliferative activity. Compound 3 possessed the best ability to induce HepG2 apoptosis. Also, ADMET calculations were performed in silico, and the results revealed that compound 3 has more suitable characteristics as a potential drug candidate.

Quinoline Derivatives as Promising Scaffolds for Antitubercular Activity: A Comprehensive Review.

Heterocyclic compounds and their derivatives play a significant role in the design and development of novel quinoline drugs. Among the various pharmacologically active heterocyclic compounds, quinolines stand out as the most significant rings due to their broad pharmacological roles, specifically antitubercular activity, and their presence in plant-based compounds. Quinoline is characterized by a benzene ring fused to a pyridine ring, with both rings sharing two adjacent carbon atoms. Other names, such as benzpyridine, benzopyridine, and 1-azanaphthalene also know it. The importance of quinoline lies in its incorporation as a key component in various natural compounds found in medicinal plant families like Fumariaceae, Berberidaceae, Rutaceae, Papavaraceae, and others. This article is expected to have a significant impact on the advancement of effective antitubercular medications. Through harnessing the potent activity of quinoline derivatives, the research aims to make valuable contributions to combating tuberculosis more efficiently and ultimately reducing the global burden of this infectious disease. Numerous nitrogen-containing heterocyclic compounds exhibit significant potential as antitubercular agents. These chemicals have fused aromatic nitrogen-heterocyclic nuclei that can change the number of electrons they have, which can change their chemical, physical, and biological properties. This versatility arises from their ability to bind to receptors in multiple modes, a critical aspect of drug pharmacological screening. Among these compounds, quinoline stands out as it incorporates a stable fusion of a benzene ring with a pyridine nucleus. Quinolines have demonstrated a diverse range of pharmacological activities, including but not limited to anti-tubercular, antitumor, anticoagulant, anti-inflammatory, antioxidant, antiviral, antimalarial, anti-HIV, and antimicrobial effects. Some molecules, such as lone-paired nitrogen species, include pyrrole, pyrazole, and quinoline. These molecules contain oxygen and take part in metabolic reactions with other molecules inside the cell. However, an excessive accumulation of reactive nitrogen species can lead to cytotoxicity, resulting in damage to essential biological macromolecules. Among these compounds, quinoline stands out as the oldest and most effective one, exhibiting a wide range of beneficial properties such as antitubercular, antimicrobial, anti-inflammatory, antioxidant, analgesic, and anticonvulsant activities. Notably, naturally occurring quinoline compounds, such as quinine, have proven to be potent antimalarial drugs. This review highlights quinoline derivatives' antitubercular potential, emphasizing recent research advancements. Utilizing IC50 values, the study underscores the efficacy of various quinoline substitutions, hybrids, and electron-withdrawing groups against MTB H37Rv. Continued research is essential for developing potent, low-toxicity quinoline derivatives to combat tuberculosis.

Synthesis of β-Amino Carbonyl 6-(Aminomethyl)- and 6-(Hydroxymethyl)pyrazolopyrimidines for DPP-4 Inhibition Study.

Type-2 diabetes is a chronic progressive metabolic disease resulting in severe vascular complications and mortality risk. Recently, DPP-4 inhibitors are conceived as a favorable class of agents for the treatment of type 2 diabetes due to the minimal side effects. Sitagliptin is the first medicine approved for DPP-4 inhibitor. Its structure involved three fragments: 2,4,5-triflorophenyl fragment pharmacophore, enantiomerically β-amino carbonyl linker, and tetrahydrotriazolopyridine. Herein, we are drawn to the possibility of substituting tetrahydrotriazolopyridine motif present in Sitagliptin with a series of new fused pyrazolopyrimidine bicyclic fragment to investigate potency and safety. Two series of fused 6-(aminomethyl)pyrazolopyrimidine and 6-(hydroxymethyl)pyrazolopyrimidine derivatives containing β-amino ester or amide as linkers were successfully designed for the new DPP-4 inhibitors. Most fused 6-methylpyrazolopyrimidines were evaluated against DPP-4 inhibition and selectivity capacity. Based on research study, β-amino carbonyl fused 6-(hydroxymethyl)pyrazolopyrimidine possesses the significant DPP-4 inhibition (IC50 ≤ 59.8 nM) and presents similar with Sitagliptin (IC50 = 28 nM). Particularly, they had satisfactory selectivity over DPP-8 and DPP-9, except for QPP. β-Amino esters and amides fused 6-(hydroxymethyl)pyrazolopyrimidine were developed as the new DPP-4 inhibitors. Those compounds with a methyl group or hydrogen in N-1 position and methyl substituted group in C-3 of pyrazolopyrimidine moiety showed better potent DPP-4 inhibition (IC50 = 21.4-59.8 nM). Furthermore, they had satisfactory selectivity over DPP-8 and DPP-9 Finally, the docking results revealed that compound 9n was stabilized at DPP-4 active site and would be a potential lead drug.

Exploration and Validation of Lead Molecules against Yellow Fever through High Throughput Virtual Screening and Molecular Dynamics Simulation

Background: Yellow fever (YF) is a mosquito-borne flaviviral hemorrhagic fever (VHF) that causes severe hepatitis, renal failure, bleeding, and quick terminal events such as shock and multi-organ failure. There are currently no particular anti-viral medications for the management of the YF virus (YFV). Despite the availability of a commercial YFV vaccination, there are roughly 30,000 fatalities globally each year, with instances rising over the previous 20 years. After being translocated into the endoplasmic reticulum lumen, glycosylated NS1 resides as a membrane-associated dimer, where it is required for viral genome replication. The secreted hexamer NS1 has a role in immune evasion and pathogenesis and has been discovered as a possible diagnostic marker for the early identification of viral infections. Objective: The main aim of this study is to analyze the small molecule as a potent drug candidate against the target NS1 protein. Methods: In this study, Computational approaches, including high throughput virtual screening, molecular docking, and dynamics simulation, were carried out against the target NS1 protein using three different chemical libraries Enamine, Asinex, and NCI. The selected lead compounds were validated through HOMO-LUMO analysis, ADME prediction, and Toxicity parameters to analyze the biological and pharmacological properties of the lead small molecules. Results: From the result, it was concluded that the leads possessed the highest docking scores, interacting with the binding residues, and were stable in the simulation period. Conclusion: Overall findings revealed that the lead three small molecules could act as the potential drug candidate for the target NS1 protein to inhibit the diseasing efficacy of Yellow fever.

A Network Pharmacology Approach and Validation Experiments to Investigate the Mechanism of Wen-Dan Decoction in the Treatment of SINFH

Introduction:: Steroid-induced necrosis of the femoral head (SINFH) is a femoral head necrotic disease caused by prolonged use of hormones. Wen-Dan decoction is used in Chinese clinical practice for the treatment of steroid-induced necrosis of the femoral head (SINFH). However, the mechanism and active compounds of Wen-Dan decoction used to treat SINFH are not well understood. Objectives:: We studied the mechanism of action of Wen-Dan decoction in treating steroidinduced necrosis of the femoral head (SINFH) via network pharmacology and in vivo experiments. Methods:: The active compounds of Wen-Dan decoction and SINFH-related target genes were identified through public databases. Then, network pharmacological analysis was conducted to explore the potential key active compounds, core targets and biological processes of Wen-Dan decoction in SINFH. The potential mechanisms of Wen-Dan decoction in SINFH obtained by network pharmacology were validated through in vivo experiments. Results:: We identified 608 DEGs (differentially expressed genes) (230 upregulated, 378 downregulated) in SINFH. GO analysis revealed that the SINFH-related genes were mainly involved in neutrophil activation and the immune response. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that the SINFH-related genes were mainly associated with cytokine receptor interactions, lipids, atherosclerosis, and tuberculosis. We identified 147 active ingredients of Wen-Dan decoction; the core ingredient was quercetin, and licorice was an active ingredient. Moreover, 277 target genes in the treatment of SINFH with Wen-Dan decoction were identified, and NCF1, PTGS2, and RUNX2 were selected as core target genes. QRT-PCR of peripheral blood from SINFH patients showed higher levels of PGTS2 and NCF1 and showed lower levels of RUNX2 compared to controls. QRT-PCR analysis of peripheral blood and femoral bone tissue from a mouse model of SINFH showed higher levels of PGTS2 and NCF1 and lower levels of RUNX2 in the experimental animals than the controls, which was consistent with the bioinformatics results. HE, immunohistochemistry, and TUNEL staining confirmed a significant reduction in hormone-induced femoral head necrosis in the quercetintreated mice. HE, immunohistochemistry, and TUNEL staining confirmed significant improvement in hormone-induced femoral head necrosis in the quercetin-treated mice. Conclusion:: We provide new insights into the genes and related pathways involved in SINFH and report that PTGS2, RUNX2, and NCF1 are potential drug targets. Quercetin improved SINFH by promoting osteogenesis and inhibiting apoptosis.

Recent Advances in the Development of RET Inhibitors

Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase, causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions. Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib were approved by FDA for the treatment of RET-altered tumors. Objective: Recently reported RET inhibitors were reviewed to provide an overview of the development of novel RET inhibitors. Methods: Literatures, patents, and conference proceedings published in the past five years were collected. Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzymebased and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected RET inhibitors were described. Results: Great efforts have been spent on the development of RET inhibitors, leading to increased RETtargeted therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8- month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants, TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies. Conclusion: Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three promising strategies to address the potential drug resistance of RET.

NOX-2 Inhibitors may be Potential Drug Candidates for the Management of COVID-19 Complications.

COVID-19 is an RNA virus that attacks the targeting organs, which express angiotensin-converting enzyme-2 (ACE-2), such as the lungs, heart, renal system, and gastrointestinal tract. The virus that enters the cell by endocytosis triggers ROS production within the confines of endosomes via a NOX-2 containing NADPH-oxidase. Various isoforms of NADPH oxidase are expressed in airways and alveolar epithelial cells, endothelial and vascular smooth muscle cells, and inflammatory cells, such as alveolar macrophages, monocytes, neutrophils, and T-lymphocytes. The key NOX isoform expressed in macrophages and neutrophils is the NOX-2 oxidase, whereas, in airways and alveolar epithelial cells, it appears to be NOX-1 and NOX-2. The respiratory RNA viruses induce NOX-2-mediated ROS production in the endosomes of alveolar macrophages. The mitochondrial and NADPH oxidase (NOX) generated ROS can enhance TGF-β signaling to promote fibrosis of the lungs. The endothelium-derived ROS and platelet-derived ROS, due to activation of the NADPH-oxidase enzyme, play a crucial role in platelet activation. It has been observed that NOX-2 is generally activated in COVID-19 patients. The post-COVID complications like pulmonary fibrosis and platelet aggregation may be due to the activation of NOX-2. NOX-2 inhibitors may be a useful drug candidate to prevent COVID-19 complications like pulmonary fibrosis and platelet aggregation.

Network pharmacology and biochemical experiments reveal the antiapoptotic mechanism of huperzine A for treating diabetic retinopathy

Background/aimsDiabetic retinopathy is the most common eye disease that causes blindness in the working population. Neurodegeneration is the early sign of diabetic retinopathy, but no drug has been approved for...

Computational Drug Discovery in Diaphragm dysfunction via Text Mining and Biomedical Database.

The diaphragm, which is crucial for ventilation, is the primary muscle responsible for inspiration. Patients with severe burns who experience diaphragmatic dysfunction have an increased risk of mortality. Unfortunately, there are currently no effective medications available to prevent or treat this condition. The objective of our study is to utilize bioinformatics to identify potential genes and drugs associated with diaphragmatic dysfunction. In this study, text mining techniques were utilized to identify genes associated with diaphragmatic dysfunction and recovery. Common genes were then analyzed using GO and KEGG pathway analysis, as well as protein-protein interaction (PPI) network analysis. The obtained hub genes were processed using Cytoscape software, and their expression levels in diaphragmatic dysfunction were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in severe burn rats. Genes that were confirmed were then examined in drug-gene interaction databases to identify potential drugs associated with these genes. Our analysis revealed 96 genes that were common to both the "Diaphragm dysfunction" and "Functional Recovery" text mining concepts. Gene enrichment analysis identified 19 genes representing ten pathways. qRT-PCR showed a significant increase in expression levels of 13 genes, including CCL2, CCL3, CD4, EGF, HGF, IFNG, IGF1, IL17A, IL6, LEP, PTGS2, TGFB1, and TNF, in samples with diaphragmatic dysfunction. Additionally, we found that a total of 56 drugs targeted 5 potential genes. These findings provide new insights into the development of more effective drugs for treating diaphragmatic dysfunction, and also present substantial opportunities for researching new target pharmacology and promoting drugs in the pharmaceutical industry.

The Genetic Architecture of Biological Age in Nine Human Organ Systems.

Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10 -8 ) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud's Conjecture 1 - the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer's disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine .

A Computational Modeling Study on the Biomolecular Interactions of the Phytoconstituents of Nigella sativa with Anti-Apoptotic Proteins Mcl-1 and Bcl-x1

Cancer is the second leading cause of mortality worldwide. The strictly controlled physiological process of apoptosis is required for immune system function, maintenance of tissue homeostasis, and appropriate embryonic development. Anti-apoptotic proteins such as Bcl-xL and Mcl-1 are potent new anticancer targets. The inhibitory effect of the apparently therapeutic plant Nigella sativa on these targets is investigated using a molecular modeling approach in this work. From the molecular docking, we predict that seven compounds; apigenin, chlorogenic acid, hesperidin, quercetin, quercitrin, kaempferol, and rutin may have greater inhibitory potential against the target protein. These compounds have higher docking scores thus indicating higher binding affinities when compared to co-crystallized compounds. The co-compounds were crystallized with the standards, which served as the baselines for comparison studies. This result shows that that Nigella sativa compounds may be a potential anticancer drug that targets the anti-apoptotic protein. Targeting anti-apoptotic proteins provides clinical studies with the opportunity to evaluate for possible anti-cancer potential in the plant via other experimental models like rats and cancer cell lines. Using phytomedicines can equally augment existing therapy to provide synergistic anti-cancer effect when combined with existing drugs thereby enhancing therapy efficacy and because medicinal plants has lots of phytoconstituents, its use in this research can provide benefits of targeting multiple anti-apoptotic proteins thereby enhancing therapeutic effect unlike some conventional drugs that are mostly single targeting.

Prevalence, Incidence and Treatment Patterns of Prurigo Nodularis in England: A Retrospective Database Analysis.

Prurigo nodularis (PN) is a pruritic skin disease characterised by multiple, intensely itchy skin nodules in symmetrically distributed areas of the extremities. There are very limited studies on the epidemiology and treatment pathways for PN, especially moderate-to-severe PN, from England. To assess the epidemiology and treatment pathways of mild and moderate-to-severe PN in England. This retrospective cohort study used data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) in England. Adult patients (≥18 years) with a PN specific diagnosis code any time between 1 April 2007 and 1 March 2019 (patient identification period) were selected. Patients were included if their first PN diagnostic code (index diagnosis date, IDD) was recorded during the identification period, with data available 6 months pre- and ≥12 months post-IDD. Patients were classified into moderate-to-severe PN (MSPN) or mild PN (MiPN) based on the presence or absence of a prescription record, post IDD, for either a systemic immunosuppressant or a gabapentinoid. Patients with MSPN and MiPN were matched 1:1 for age, gender and IDD. Prevalence and incidence were calculated for each year from 2007 to 2019. Drugs prescribed post IDD were analysed. A total of 8,933 patients (MSPN: 2,498 patients; MiPN: 6,539 patients) were included for the study; 2,462 patients each with MiPN and MSPN were included for the comparative analysis. Atopic dermatitis, asthma and eosinophilic oesophagitis were significantly higher (all p<0.001) in patients with MSPN (vs MiPN). The prevalence of overall PN cases increased during the study period. The incidence rate also showed a similar trend. The rates of prescription of potent and super potent topical corticosteroids (TCS), topical calcineurin inhibitors, first- and second- generation antihistamines, oral and injectable systemic corticosteroid, methotrexate, antidepressants and tacrolimus were significantly higher (all p <0.001) in patients with MSPN (vs MiPN). The epidemiology of PN was consistent with other European studies. Patients with MSPN received a significantly higher number of prescriptions for potent TCS and systemic drugs, as compared with milder patients.

High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma

Type I interferon (IFN) is a potent antitumoral drug, with an important history in the treatment of hematologic malignancies. However, its pleiotropic nature leads to severe dose-limiting toxicities that blunt its therapeutic potential. To achieve selective targeting of specific immune or tumor cells, AcTakines (Activity-on-Target Cytokines), i.e., immunocytokines utilizing attenuated cytokines, and clinically optimized A-Kines™ were developed. In syngeneic murine models, the CD20-targeted murine IFNα2-based AcTaferons (AFNs) have demonstrated clear antitumoral effects, with excellent tolerability. The current study explores the antitumoral potential of the humanized huCD20-Fc-AFN in 5 different humanized patient derived xenograft (PDX) models of huCD20+ aggressive B non-Hodgkin lymphomas (B-NHLs). The huCD20-Fc-AFN consists of a huCD20-specific single-domain antibody (VHH) linked through a heterodimeric ‘knob-in-hole’ human IgG1 Fc molecule to an attenuated huIFNα2 sequence. An in vitro targeting efficacy of up to 1.000-fold could be obtained, without detectable in vivo toxicities, except for selective (on-target) and reversible B cell depletion. Treatment with huCD20-Fc-AFN significantly increased the median overall survival (mOS) in both non-humanized (mOS 31 to 45 days; HR = 0.26; p = 0.001), and humanized NSG/NOG mice (mOS 34 to 80 days; HR = 0.37; p < 0.0001). In humanized mice, there was a trend for increased survival when compared to equimolar rituximab (mOS 49 to 80 days; HR = 0.73; p = 0.09). The antitumoral effects of huCD20-Fc-AFN were partly due to direct effects of type I IFN on the tumor cells, but additional effects via the human immune system are essential to obtain long-term remissions. To conclude, huCD20-Fc-AFN could provide a novel therapeutic strategy for huCD20-expressing aggressive B-NHLs.Graphical

The safety and efficacy of diclofenac sodium suppository as adjunctive opioids in the treatment of cancer pain: A prospective, multi-center, real-world study.

12055 Background: Cancer pain is one of the most common and unbearable symptoms for cancer patients (pts), seriously affecting their quality of life. Diclofenac sodium is a potent third-generation non-steroidal anti-inflammatory drug known for its significant analgesic, anti-inflammatory, and antipyretic effects. It is commonly used to treat different types of cancer pain. The objective of this study was to assess the safety and effectiveness of diclofenac sodium suppository when used alongside opioids for managing cancer pain in pts with solid tumors. Methods: In this prospective, multi-center, real-world study, we enrolled pts diagnosed with malignancy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-3, numeric rating scale (NRS) score ≥ 3, and sustained cancer pain, who required additional analgesic medication were enrolled. Diclofenac sodium suppository is an anal administration suppository, prescribed once a day at a dosage of 50 mg. This study was conducted across 20 centers to observe the clinical characteristics of pain relief in pts with cancer pain . The primary endpoint of the study was to assess the safety of the medication. The secondary endpoints included evaluating the incidence of breakthrough pain (BP), NRS score, and Brief Pain Inventory (BPI) score on the second and sixth days of medication. Results: Of the 506 pts that were screened, 437 pts met the inclusion criteria. This included 10 pts who did not receive planned treatment and 2 pts who did not undergo post-baseline efficacy evaluation. Among the 425 pts in the full analysis set (FAS), 261 were man, and 169 (39.8%) had baseline BP. The mean age was 63.0±11.3 years old. Among 425 response-evaluable pts, compared to the baseline, the incidence of BP was reduced on the second (20.0% vs 39.8%), and sixth days (14.8% vs 39.8%) of medication and the difference was statistically significant ( P &lt; 0.001, P &lt; 0.001). For pts with baseline BP, 56.2% and 66.9% pts achieved BP relief on the second and sixth days of medication, respectively. From the baseline evaluation, the mean NRS scores for the three visits (baseline, second day, sixth day) were 5.28 ± 1.71, 3.73 ± 1.71, and 2.91 ± 1.88, respectively. The mean pain intensity at each visit was decreased compared to the baseline, and the difference was statistically significant ( P &lt; 0.001, P &lt; 0.001). 427 pts were included for safety analysis and 5 pts experienced any grade treatment emergent adverse events (TEAEs). All TEAEs were grade 1-2. TEAE leading to treatment discontinuation was occurred in one pt. Conclusions: This study demonstrated that diclofenac sodium suppository was an effective treatment option for managing breakthrough pain in patients with persistent cancer pain who required additional analgesic therapy. Moreover, diclofenac sodium suppository was found to be well tolerated when administered anally.

Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications.

Metabolic reprogramming of cells, from the normal mode of glucose metabolism named glycolysis, is a pivotal characteristic of impending cancerous cells. Pyruvate kinase M2 (PKM2), an important enzyme that catalyzes the final rate-limiting stage during glycolysis, is highly expressed in numerous types of tumors and aids in development of favorable conditions for the survival of tumor cells. Increasing evidence has suggested that PKM2 is one of promising targets for innovative drug discovery, especially for the developments of antitumor therapeutics. Herein, we systematically summarize the recent advancement on PKM2 modulators including inhibitors and activators in cancer applications. We also discussed the classifications of pyruvate kinases in mammals and the biological functions of PKM2 in this review. We do hope that this review would provide a comprehensive understanding of the current research on PKM2 modulators, which may benefit the development of more potent PKM2-related drug candidates to treat PKM2-associated diseases including cancers in future.

Botanical Extracts and Compounds of Castanea Plants and Methods of Use: US20190125818A1 - The United States Patent Evaluation.

Bacterial infections are increasingly difficult to combat, which makes them a threat to public health on a global level. Staphylococcus aureus is considered one of the main causes of infections in hospitals, as it has a variety of virulence factors, as well as is able to produce bacterial biofilms, which, consequently, bring numerous damages to public health as a result of increased resistance to conventional antibiotics and a longer hospital stay. Therefore, the use of compounds extracted from medicinal plants is a potential pharmaceutically acceptable target, as they do not have toxicity and the potential to disrupt biofilms produced by Staphylococcus aureus already evidenced, thus revealing their relevance to our study. The objective of this work was to perform a critical analysis of a patent with natural extracts against bacterial biofilms found in the United States Patent and Trademark Office (USPTO) database, to map the possible bioactive compounds that may serve as potential future antimicrobial drugs. A technological survey was carried out to verify existing patents using natural extracts with anti-biofilm potential. For this, it was searched with the keywords: Botanical extracts AND biofilms; which were performed in the United States Patent and Trademark Office (USPTO) database. Thus, the selected patent used a non-aqueous extract partitioned and vacuum-contracted, subsequently lyophilized for assays with antimicrobial potential. Because of this, a patent was analyzed regarding its chemistry, and biological activity, followed by a critical analysis of the technology proposed in the invention. When using the keywords Botanical extracts AND biofilms in the USPTO, it was possible to find twenty-two inventions; however, only four patents in the USPTO were in agreement with the proposal of the natural extract having antimicrobial activity and an anti-biofilm potential, of which two belonged to the same applicant with similar proposals. The key point of this invention was to enable the compounds of the Castanea sativa plant and its methods of obtaining the extract to present a significant antimicrobial action associated or not with antibiotics, promoting the development of new therapies against bacterial infections capable of disrupting biofilms. The invention developed a methodology for extracting Castanea sativa, in which pentacyclic triterpene compounds were found mostly in its leaves. Whereas for the extraction, the crude methanol extracts called extracts 224 from the ground leaves were made by maceration, filtered, combined, concentrated under pressure in rotary evaporators, and lyophilized. After that, they were resuspended in water and partitioned in succession with hexane, ethyl acetate, and butanol. The most active refined partition was the 224C extract with the solvent ethyl acetate, which was subjected to further fractionation using silica column chromatography. Resulting in the most refined extract, which was 224C-F2, capable of acting directly on the quorum sensing of bacteria, mainly Staphylococcus aureus, blocking the translation of RNAIII, including a series of exotoxins. Regarding the antimicrobial capacity against Staphylococcus aureus, it presented Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of 1.56 μg/mL-1 and > 100 μg/mL -1, respectively. Given the analyzed patent, it was possible to verify the importance of alternatives to reduce the impact of bacterial biofilms, which causes damage to industries in general and to health. From this, the invention analyzed has a promising proposal with antimicrobial potential focusing on the great impact of bacterial biofilms. Therefore, natural extracts with antibiofilmic potential can help to minimize the economic losses caused to health due to these multidrug-resistant microorganisms with different virulence mechanisms.

Prediction of SARS-CoV-2 Infection Phosphorylation Sites and Associations of these Modifications with Lung Cancer Development.

Since the emergence of SARS-CoV-2 viruses, multiple mutant strains have been identified. Infection with SARS-CoV-2 virus leads to alterations in host cell phosphorylation signal, which systematically modulates the immune response. Identification and analysis of SARS-CoV-2 virus infection phosphorylation sites enable insight into the mechanisms of viral infection and effects on host cells, providing important fundamental data for the study and development of potent drugs for the treatment of immune inflammatory diseases. In this paper, we have analyzed the SARS-CoV-2 virus-infected phosphorylation region and developed a transformer-based deep learning-assisted identification method for the specific identification of phosphorylation sites in SARS-CoV-2 virus-infected host cells. Furthermore, through association analysis with lung cancer, we found that SARS-CoV-2 infection may affect the regulatory role of the immune system, leading to an abnormal increase or decrease in the immune inflammatory response, which may be associated with the development and progression of cancer. We anticipate that this study will provide an important reference for SARS-CoV-2 virus evolution as well as immune-related studies and provide a reliable complementary screening tool for anti-SARS-CoV-2 virus drug and vaccine design.

Exploratory Study of Differentially Expressed Genes of Peripheral Blood Monocytes in Patients with Carotid Atherosclerosis.

The abundance of circulating monocytes is closely associated with the development of atherosclerosis in humans. This study aimed to further research into diagnostic biomarkers and targeted treatment of carotid atherosclerosis (CAS). We performed transcriptomics analysis through weighted gene co-expression network analysis (WGCNA) of monocytes from patients in public databases with and without CAS. Differentially expressed genes (DEGs) were screened by R package limma. Diagnostic molecules were derived by the least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) algorithms. NetworkAnalyst, miRWalk, and StarBase databases assisted in the construction of diagnostic molecule regulatory networks. The DrugBank database predicted drugs targeting the diagnostic molecules. RT-PCR tested expression profiles. From 14,369 hub genes and 61 DEGs, six differentially expressed monocyte-related hub genes were significantly associated with immune cells, immune responses, monocytes, and lipid metabolism. LASSO and SVM-RFE yielded five genes for CAS prediction. RT-PCR of these genes showed HMGB1 was upregulated, and CCL3, CCL3L1, CCL4, and DUSP1 were down-regulated in CAS versus controls. Then, we constructed and visualized the regulatory networks of 9 transcription factors (TFs), which significantly related to 5 diagnostic molecules. About 11 miRNAs, 19 lncRNAs, and 39 edges centered on four diagnostic molecules (CCL3, CCL4, DUSP1, and HMGB1) were constructed and displayed. Eleven potential drugs were identified, including ibrutinib, CTI-01, roflumilast etc. Conclusion: A set of five biomarkers were identified for the diagnosis of CAS and for the study of potential therapeutic targets.

Harnessing Computational Modeling for Efficient Drug Design Strategies

Abstract: Computational modeling has become a crucial tool in drug design, offering efficiency and cost-effectiveness. This paper discusses the various computational modeling techniques used in drug design and their role in enabling efficient drug discovery strategies. Molecular docking predicts the binding affinity of a small molecule to a target protein, allowing the researchers to identify potential lead compounds and optimize their interactions. Molecular dynamics simulations provide insights into protein-ligand complexes, enabling the exploration of conformational changes, binding free energies, and fundamental protein-ligand interactions. Integrating computational modeling with machine learning algorithms, such as QSAR modeling and virtual screening, enables the prediction of compound properties and prioritizes potential drug candidates. High-performance computing resources and advanced algorithms are essential for accelerating drug design workflows, with parallel computing, cloud computing, and GPU acceleration reducing computational time. The paper also addresses the challenges and limitations of computational modeling in drug design, such as the accuracy of scoring functions, protein flexibility representation, and validation of predictive models. It emphasizes the need for experimental validation and iterative refinement of computational predictions to ensure the reliability and efficacy of designed drugs.