Potential Drug Candidates Research Articles

Identification of novel biomarkers, shared molecular signatures and immune cell infiltration in heart and kidney failure by transcriptomics.

Heart failure (HF) and kidney failure (KF) are closely related conditions that often coexist, posing a complex clinical challenge. Understanding the shared mechanisms between these two conditions is crucial for developing effective therapies. This study employed transcriptomic analysis to unveil molecular signatures and novel biomarkers for both HF and KF. A total of 2869 shared differentially expressed genes (DEGs) were identified in patients with HF and KF compared to healthy controls. Functional enrichment analysis was performed to explore the common mechanisms underlying these conditions. A protein-protein interaction (PPI) network was constructed, and machine learning algorithms, including Random Forest (RF), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Least Absolute Shrinkage and Selection Operator (LASSO), were used to identify key signature genes. These genes were further analyzed using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA), with their diagnostic values validated in both training and validation sets. Molecular docking studies were conducted. Additionally, immune cell infiltration and correlation analyses were performed to assess the relationship between immune responses and the identified biomarkers. The functional enrichment analysis indicated that the common mechanisms are associated with cellular homeostasis, cell communication, cellular replication, inflammation, and extracellular matrix (ECM) production, with the PI3K-Akt signaling pathway being notably enriched. The PPI network revealed two key protein clusters related to the cell cycle and inflammation. CDK2 and CCND1 were identified as signature genes for both HF and KF. Their diagnostic value was validated in both training and validation sets. Additionally, docking studies with CDK2 and CCND1 were performed to evaluate potential drug candidates. Immune cell infiltration and correlation analyses highlighted the immune microenvironment, and that CDK2 and CCND1 are associated with immune responses in HF and KF. This study identifies CDK2 and CCND1 as novel biomarkers linking cell cycle regulation and inflammation in heart and kidney failure. These findings offer new insights into the molecular mechanisms of HF and KF and present potential targets for diagnosis and therapy.

P38α Mitogen-Activated Protein Kinase-An Emerging Drug Target for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment.

Elucidation of the molecular mechanism of type 2 diabetes mellitus affecting the progression of nonalcoholic steatohepatitis using bioinformatics and network pharmacology: A review.

Increasing evidence suggests that patients with diabetes are at increased risk of developing nonalcoholic steatohepatitis (NASH), but the underlying mechanisms that affect the progression of NASH remain unclear. In this study, we used bioinformatics and network pharmacology methods to explore the differentially expressed genes of NASH and the related genes of type 2 diabetes mellitus, and a total of 46 common targets were obtained. Gene ontology showed that the common targets were mainly involved in biological processes such as glucocorticoid, hormone, and bacterium responses. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis signal pathways were mainly in colorectal cancer, amphetamine addition, the peroxisome proliferator-activated receptor signaling pathway, and the toll-like receptor signaling pathway. The protein-protein interaction network identified 8 hub genes, and the co-expression network was analyzed to obtain 7 related functions and mutual proportions of hub genes. A total of 120 transcription factors were predicted for hub genes. Hub genes were closely related to immune cells, including neutropils and eosinophils. In addition, we identified 15 potential candidate drugs based on hub genes that are promising for the treatment of NASH. Type 2 diabetes mellitus can affect the progression of NASH by changing hormone levels and inflammatory responses through multiple targets and signaling pathways. Eight hub genes are expected to be potential targets for subsequent treatment.

Development of a scintillation proximity assay for [3H]epibatidine binding sites of Tetronarce californica muscle-type nicotinic acetylcholine receptor

The therapy of intoxication with distinct organophosphorus (OP) compounds is still limited today. Especially chemical warfare agents like tabun and soman as well as novichok intoxications are difficult to address using established oxime therapeutics. These neurotoxins inhibit acetylcholinesterase (AChE), a pivotal enzyme in the synaptic cleft. The following accumulation of acetylcholine in the synaptic cleft leads to a dysfunctional, desensitized state of nicotinic acetylcholine receptors (nAChR). Without adequate treatment, the resulting cholinergic crisis leads to death by respiratory arrest. Consequently, the research approach for new therapeutic options needs to be expanded. A promising option would be substances interacting directly with nAChRs. Therefore, screening methods for new drug candidates are needed, with affinity assays playing an important role. In the present work, a saturation and competition scintillation proximity assay (SPA) for binding studies at [3H]epibatidine binding sites, conventionally classified as orthosteric binding sites of the muscle type nAChR was developed. This method offers several advantages over other assay technologies because no separation as well as washing steps are required to remove unbound ligands. Assay precision and solvent tolerance were validated according to the guidelines for validation of bioanalytical methods of the Food and Drug Administration (FDA) and European Medicines Agency (EMA). The newly developed binding assay was successfully implemented on an automated pipetting platform and is suitable for high-throughput-screening of receptor-ligand interactions at the nAChR. Furthermore, it allows to investigate/quantify competition of highly toxic agents such as nerve agents or structurally similar pesticides at the orthosteric binding site. Related to further pharmacological results, the affinity to [3H]epibatidine binding sites can provide additional information on whether potential drug candidates would be suitable for treatment of nerve agent poisoning.

Synthesis and antimicrobial activity of benzoxazine/benzothiazine appended 1,2,3-triazole hybrids

In the present context to rationalize the search for new effective antimicrobial agents against the infections caused by microbes, a series of benzoxazine/benzothiazine appended 1,2,3-triazole hybrids were designed and synthesized via click reaction with ingredients of two or more bioactive moieties through the concept of molecular hybridization. Various spectral techniques such as FTIR, 1H NMR, 13C NMR, 2D NMR and HRMS were utilized for structural elucidation of the synthesized hybrids. The serial dilution method was employed for performing the antimicrobial activity of synthesized triazoles against four bacterial (S. aureus, B. subtilis, E. coli, K. pneumoniae) and two fungal (C. albicans, A. niger) strains. The antibacterial results demonstrated that a couple of hybrids show noteworthy outcomes related to standard medication. Compound 4r was indicated great action against E. coli with MIC values 0.0259 µmol/mL. Based on outcomes of antibacterial activity, molecular docking study was carried out with E. coli DNA gyrase to understand the binding behavior. To check out the drug-likeness, in silico ADME (Absorption, Distribution, Metabolism and Excretion) studies of synthesized hybrids were also analyzed and found that compounds can be developed as potential oral drug candidates.

Neuropeptide Network of Polycystic Ovary Syndrome - A Review.

Polycystic Ovary Syndrome (PCOS), the ubiquitous reproductive disorder, has been documented as highly prevalent (6-9%) in India. 10% of women globally are predicted to have the disease. The highly mutable endocrinopathy, with differential clinical criteria for each diagnosis of PCOS, can mask the severity of the syndrome by influencing the incidence and occurrence of PCOS. When there is a solid theoretical hypothesis between the neuroendocrine origin and ovarian origin of PCOS, recent evidence supports the neuroendocrine derivation of the pathology. It is considered of neuroendocrine basis - as it controls the ovarian axis and acts as a delicate target because it possesses receptors for various gonadal hormones, neurotransmitters & neuropeptides. Can these neuroendocrine alterations, variations in central brain circuits, and neuropeptide dysregulation be the tie that would link the pathophysiology of the disorder, the occurrence of all the 1˚ and 2˚ symptoms like polycystic ovaries, hyperandrogenism, obesity, insulin resistance, etc., in PCOS? This review anticipates providing a comprehensive overview of how neuropeptides such as Kisspeptin, Neurokinin B, Dynorphin A, β-Endorphin, Nesfatin, Neuropeptide Y, Phoenixin, Leptin, Ghrelin, Orexin, and Neudesin influence PCOS, the understanding of which may help to establish potential drug candidates against precise targets in these central circuits.

Suppression of ZEB1 by Ethyl caffeate attenuates renal fibrosis via switching glycolytic reprogramming

Renal fibrosis (RF) is a common endpoint of various chronic kidney diseases, leading to functional impairment and ultimately progressing to end-stage renal failure. Glycolytic reprogramming plays a critical role in the pathogenesis of fibrosis, which maybe a potential therapeutic target for treating renal fibrosis. Here, we revealed the novel role of ZEB1 in renal fibrosis, and whether targeting ZEB1 is the underlying mechanism for the anti-fibrotic effects of ethyl caffeate (EC) to regulate the glycolytic process. Treatment of EC attenuated the renal fibrosis and inhibited ZEB1 expression in vivo and in vitro, reducing the upregulated expression of glycolytic enzymes (HK2, PKM2, PFKP) and key metabolites (lactic acid, pyruvate). ZEB1 overexpression promoted the renal fibrosis and glycolysis, whereas knockout of ZEB1 apparently attenuated renal fibrosis in vivo and in vitro. EC interacted with ZEB1 to modulate the glycolytic enzymes for suppressing the elevated glycolytic reprogramming during renal fibrosis. In summary, our study reveals that ZEB1 plays an important role in regulating glycolytic reprogramming during the renal tubular epithelial cell fibrosis, suggesting inhibition of ZEB1 may be a potential strategy for treating renal fibrosis. Additionally, EC is a potential new drug candidate for the treatment of renal fibrosis and CKD.

Comprehensive computational and pharmacokinetic investigation of an amide derivative (C34H34N8O4S2) as a potential drug candidate for tuberculosis: Unraveling structural analysis and reactivity descriptors

Despite the early success of tuberculosis combination therapies, which have high cure rates and low relapse rates, drug-resistant strains of Mycobacterium tuberculosis have continued to emerge in both high- and low-incidence regions. This has made the exploration of antitubercular compounds highly important; thus, the present study explored the antitubercular activities of amide derivatives (BTPs). This research utilized computational techniques, particularly DFT at the ωB97XD/6–311++g(2d,2p) level of theory, to explore various aspects of a chemical compound, including the nature of chemical bonds and intra/intermolecular bonding analysis. The antitubercular activities of the investigated compounds were assessed through pharmacokinetics and molecular docking studies. This study reported substantial findings, beginning with high energy gaps of 8.072 eV, 8.074 eV, 7.954 eV, and 8.0736 eV for ACE, DMSO, gas, and water, respectively, defining the stability of the investigated compound. Pharmacokinetic studies revealed that carcinogenicity, hepatotoxicity, cytotoxicity, mutagenicity, and immunogenicity were all predicted to be inactive, with probabilities of P = 0.57, P = 0.97, P = 0.78, P = 0.85, and P = 0.99, respectively. Furthermore, molecular docking studies revealed that the interaction of the compound with the EmbC receptor (PDB ID: 3PTY) resulted in a good binding affinity of −7.0 kcal/mol with six (6) hydrogen bonds, suggesting that it is a potential candidate antitubercular compound. Therefore, the amide derivatives studied herein are recommended for exploration, particularly in in vitro and in vivo analyses.

Computational exploration of compounds in Xylocarpus granatum as a potential inhibitor of Plasmodium berghei using docking, molecular dynamics, and DFT studies

Malaria remains a global health concern, with the emergence of resistance to the antimalarial drug atovaquone through cytochrome b (cyt b) being well-documented. This study was prompted by the presence of this mutation in cyt b to enable new drug candidates capable of overcoming drug resistance. Our objective was to identify potential drug candidates from compounds of Xylocarpus granatum by computationally assessing their interactions with Plasmodium berghei cyt b. Using computational methods, we modeled cyt b (GenBank: AF146076.1), identified the binding cavity, and analyzed the Ramachandran plot against cyt b. Additionally, we conducted drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, along with density functional theory (DFT) analysis of the compounds. Molecular docking and molecular dynamics simulation (MDS) were used to evaluate the binding energy and stability of the cyt b-ligand complex. Notably, our investigation highlighted kaempferol as a promising compound due to its high binding energy of 7.67 kcal/mol among all X. granatum compounds, coupled with favorable pharmacological properties (ADMET) and antiprotozoal properties at Pa 0.345 > Pi 0.009 (PASS value). DFT analysis showed that kaempferol has an energy gap of 4.514 eV. MDS indicated that all tested ligands caused changes in bonding and affected the structural conformation of cyt b, as observed before MDS (0 ns) and after MDS (100 ns). The most notable differences were observed in the types of hydrogen bonds between 0 and 100 ns. Nevertheles, MDS results from a 100 ns simulation revealed consistent behavior for kaempferol across various parameters including root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), molecular mechanics-Poisson Boltzmann surface area (MM-PBSA), and hydrogen bonds. The cyt b-kaempferol complex demonstrated favorable energy stability, as supported by the internal energy distribution values observed in principal component analysis (PCA), which closely resembled those of the atovaquone control. Additionally, trajectory stability analysis indicated structural stability, with a cumulative eigenvalue of 24.7 %. Dynamic cross-correlation matrix (DCCM) analysis revealed a positive correlation among catalytic cytochrome residues within the amino acid residues range 119–268. The results of our research indicate that the structure of kaempferol holds promise as a potential candidate against Plasmodium.

Understanding the stability and dynamics of influenza a H5N1 polymerase PB2 CAP-Binding domain in complex with natural compounds for antiviral drug discovery

Influenza A virus, particularly the H5N1 strain, poses a significant threat to public health due to its ability to cause severe respiratory illness and its high mortality rate. Traditional antiviral drugs targeting influenza A virus have faced challenges such as drug resistance and limited efficacy. Therefore, new antiviral compounds are needed to be discovered and developed. This study concentrated on examining the stability and behavior of the H5N1 polymerase PB2 CAP-binding domain when interacting with natural compounds, aiming to identify potential candidates for antiviral drug discovery. Through the virtual screening process, four lead compounds, ZINC000096095464, ZINC000044404209, ZINC000001562130, and ZINC000059779788, were selected, and these compounds showed binding energies −9.6, −9.4, −9.3, and −9.2 kcal/mol, respectively. When complexed with PB2, the ligand showed acceptable binding stability due to significant bond formation. However, during the 200ns MD simulation analysis, three (ZINC000096095464, ZINC000044404209, and ZINC000059779788) showed significant stability, which was proven by the trajectory analysis. The Rg-RMSD-based FEL plot showed significant structural stability due to stable conformers. The free-binding energy calculation also validates the stability of these complexes. This study offers valuable insights into the stability and dynamics of the H5N1 polymerase PB2 CAP-binding domain in complexes with natural compounds. These findings highlight the potential of these natural compounds as antiviral agents against the H5N1 influenza virus. Furthermore, this research contributes to the broader field of influenza virus treatment by demonstrating the effectiveness of computational methods in predicting and evaluating the stability and dynamics of potential drug candidates.

Shared etiology of Mendelian and complex disease supports drug discovery

BackgroundDrugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease.MethodsIn previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations.ResultsOur analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated.ConclusionsOur findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.

Unveiling the bioactive potential of organotin(IV) complexes of hydrazones: Synthesis, spectral characterization, in vitro and in silico exploration

In the quest of compounds with potent antimicrobial and antioxidant properties, we conducted a comprehensive investigation involving four hydrazone ligands [H2L1–4] (1–4) and their respective sixteen organotin(IV) complexes (5–20) with general formula R″2SnL1–4 [R″ = Me, Et, Bu, Ph]. Various spectroscopic and physicochemical studies were employed for the thorough characterization of the synthesized compounds, which demonstrated the tridentate chelation of ligands via ONO donor domains by Ophenolic, Nazomethine and Oenolic atoms displaying pentacoordinated geometry. Further, the compounds were subjected to bioactivity assays by targeting their in vitro antioxidant and antimicrobial studies. Complex 8 [Ph2SnL1], 12 [Ph2SnL2], 16 [Ph2SnL3], 19 [Bu2SnL4] and 20 [Ph2SnL4] emerged as particularly noteworthy antimicrobials, exhibiting a higher level of inhibition having minimum inhibition concentration (MIC) value in the range of 0.0042–0.0095 µmol/mL. Among them, complex 20 exhibited superior activity with MIC values of 0.0042 µmol/mL against C. albicans and S. aureus, surpassing the standard drugs ciprofloxacin (0.0047 µmol/mL) and fluconazole (0.0051 µmol/mL). Additionally, all the compounds showed notable radical scavenging activity, and the activity of complexes increases in the order Ph2SnL1−4 (1.93–3.68 µM) > Bu2SnL1−4 (2.26–4.15 µM) > Et2SnL1−4 (2.91–4.97 µM) > Me2SnL1−4 (3.49–5.10 µM) (DPPH assay). Furthermore, In silico studies including Molecular docking, Density Functional Theory (DFT), Molecular Electrostatic Potential (MESP), Absorption, Distribution, Metabolism, Excretion and Toxicity ADMET) analysis highlighted the significance of highly potent antimicrobial compounds (4, 17–20) as potential drug candidates. Each compound exhibited binding affinity with protein binding site, including carbon-hydrogen bonds, conventional hydrogen bonds, alkyl interactions and pi-alkyl interactions. Compound 20 exhibited a superior docking score of −137.644 kcal/mol at the active site of C. albicans (PDB ID: 4HOE). The binding energy of the compounds followed the order: 20 (−11.6577 eV) < 19 (−11.3193 eV) < 18 (−9.23989 eV) < 17 (−8.23386 eV) < 4 (−7.01131 eV) and coincided well with the findings of experimental research. In summary, this comprehensive research underscores the substantial biological activity of the synthesized compounds and their promising potential for future applications in drug development.

Turmeric Essential Oil Constituents as Potential Drug Candidates: A Comprehensive Overview of Their Individual Bioactivities.

The therapeutic properties of turmeric essential oil have been extensively documented in both preclinical and clinical studies. Research indicates that its primary active compounds are promising candidates for addressing a wide range of pathologies, exhibiting anticancer, anti-inflammation, antioxidant, cardiovascular, hypoglycemic, dermatological, hepatoprotective, neurological, antiparasitic, antiviral, insecticidal, antifungal, and antivenom activities. While numerous compounds possess similar potential applications, the isolated active constituents of turmeric essential oil stand out due to their unique pharmacological profiles and absence of toxicity. This literature review meticulously compiles and analyzes the bioactivities of these constituents, emphasizing their molecular mechanisms of action, reported pharmacological effects, and potential therapeutic applications. The aim of this review is to provide a comprehensive synthesis of currently available clinical and preclinical findings related to individual turmeric essential oil compounds, while also identifying critical knowledge gaps. By summarizing these findings, this work encourages further research into the isolated compounds from turmeric oil as viable drug candidates, ultimately contributing to the development of innovative therapeutic strategies.

New Highly Selective Antivirals for Chikungunya Virus identified from the Screening of a Drug-Like Compound Library.

Chikungunya fever is a mosquito-borne disease caused by Chikungunya virus (CHIKV). Treatment of CHIKV infections is currently supportive and does not limit viral replication or symptoms of persistent chronic arthritis. Although there are multiple compounds reported as antivirals active against CHIKV in vitro, there are still no effective and safe antivirals. Thus, active research aims at the identification of new chemical structures with antiviral activity. Here, we report the screen of the Pandemic Response Box library of small molecules against a fully infectious CHIKV reporter virus. Our screening approach successfully identified previously reported CHIKV antiviral compounds within this library and further expanded potentially active hits, supporting the use of reporter-virus-based assays in high-throughput screening format as a reliable tool for antiviral drug discovery. Four molecules were identified as potential drug candidates against CHIKV: MMV1634402 (Brilacidin) and MMV102270 (Diphyllin), which were previously shown to present broad-spectrum antiviral activities, in addition to MMV1578574 (Eravacycline), and the antifungal MMV689401 (Fluopicolide), for which their antiviral potential is uncovered here.

Structure-Based Virtual Screening and Protein–Protein Docking Analysis of ERBB2 and Associated Proteins for Pediatric Cancer Therapeutic Approaches

Abstract Introduction The Erythroblastosis Oncogene B homolog 2 (ERBB2) protein, also known as human epidermal growth factor receptor 2 (HER2), is a key player in cancer growth, especially in neuroblastoma and gastric cancers. Targeting ERBB2 has led to successful therapies, making it an important focus in cancer research with the potential to improve treatment for HER2-positive cancers. Objective The primary goal of this research is to employ a multifaceted computational approach to identify potential drug candidates targeting ERBB2. We aim to combine virtual screening, protein–protein docking, and functional partner prediction to provide insights into the molecular interactions and potential efficacy of the identified compounds. Additionally, we intend to assess the safety profiles of these compounds using advanced toxicity prediction tools. Methods Relevant protein sequence and structural data for ERBB2 and epidermal growth factor receptor (EGFR) were sourced from publicly available databases. Potential inhibitors from the Enamine and LifeChemicals databases were identified through virtual screening using AutoDock Vina. Functional partners of ERBB2 were explored using STRING, KEGG, and REACTOME servers. The identified compounds were subjected to toxicity prediction using the ProTox-II server. Results Virtual screening led to the selection of 10 compounds with favorable binding energies (–8.346 to –6.296 kcal/mol) and specific amino acid interactions (Thr5, Arg412, Leu414, and Ser441) with the receptor. On the other hand, EGFR was identified as the best functional partner for ERBB2. The EGFR residues Gln408, Lys463, Phe412, and Asp436 found key residues for the complex formation. The toxicity prediction analysis revealed that the majority of compounds exhibited acceptable safety profiles, although a subset of compounds showed lower prediction scores, suggesting the need for further consideration. Conclusion This comprehensive computational approach, integrating virtual screening, protein–protein docking, functional partner identification, and toxicity prediction, offers a systematic framework for efficient drug discovery. The identification of potential lead compounds targeting ERBB2, with emphasis on both binding affinity and safety, underscores the significance of such an approach in streamlining the drug development process. By prioritizing compounds with promising efficacy, functional relevance, and acceptable toxicity profiles, this study advances our understanding of potential therapeutic agents, enhancing the likelihood of successful translation from computational predictions to real-world drug candidates.

Maximizing Treatment Options for IBD through Drug Repurposing.

Chronic inflammation characterizes Inflammatory Bowel Disease (IBD), encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC). Despite modest activity of disease in most UC patients, exacerbations occur, especially in those with severe symptoms, necessitating interventions, like colectomy. Current treatments for IBD, predominantly small molecule therapies, impose significant economic burdens. Drug repurposing offers a cost-effective alternative, leveraging existing drugs for novel therapeutic applications. This approach capitalizes on shared molecular pathways across diseases, accelerating therapeutic discovery while minimizing costs and risks. This article provides an overview of IBD and explores drug repurposing as a promising avenue for more effective and affordable treatments. Through computational and animal studies, potential drug candidates are categorized, offering insights into IBD pathogenesis and treatment strategies.

An efficient regioconvergent synthesis of 3-aza-obeticholic acid

Bile acids (BAs) are steroidal molecules that play important roles in nutrient absorption, distribution, and excretion. They also act on specific receptors implicated in various metabolic and inflammatory diseases demonstrating their importance as potential drug candidates. Accordingly, there has been a concerted effort to develop new BA derivatives to probe structure–activity relationships with the goal of discovering BA analogues with enhanced pharmacological properties. Among the many steroidal derivatisations reported, the formation of endocyclic azasteroids appeals due to their potential to deliver altered biological responses with minimal change to the steroidal superstructure. Here, we report the synthesis of 3-aza-obeticholic acid (6) via a regioconvergent route. Ammoniolysis of lactones, formed from an m-CPBA-mediated Baeyer-Villiger reaction on a 3-keto-OCA derivative, furnished protected intermediate amido-alcohols which were separately elaborated to amino-alcohols via Hofmann degradation with BAIB. Upon individual N-Boc-protection, these underwent annulation to the 3-aza-A-ring when subjected to either mesylation or a Dess-Martin oxidation/hydrogenation sequence. Global deprotection of the 3-aza-intermediate delivered 3-aza-OCA in ten steps and an overall yield of up to 19 %.

Crystal structures, NCI-RDG, Hirshfeld surface and energy framework analysis of tetra aryl substitute bispidine and oxaquinuclidine core containing derivatives: A potential COVID-19 drug candidate

Two of the title compounds are crystallized in P21/c and monoclinic face groups. Each crystal unit cell has four molecules. There are two piperidine rings: one in the chair conformation and another one in the boat conformation. The piperidine nitrogen in the boat conformation is joined to the oxygen-containing chair conformation piperidine ring to produce the oxaquinuclidine ring (-N-CH2O-). Furthermore, because of the steric barrier between rings, all aryl groups are oriented in an equatorial position. The crystal network is maintained through several interactions, including C—H⋯O/N/Cl/π. The crystal void and interaction energy studies gave additional evidence of the strength of the crystal packing and intermolecular linkage. Crystal 3b has less cavity than crystal 3c, indicating that it is densely packed. The dispersion energy contribution dominates the stability, according to the analysis of the electrostatic, dispersion, and total energy frameworks. Reduced density gradient (RDG), electron localization function (ELF), and localized orbital locator (LOL) analysis were used to determine the molecular interaction, electron pair density, and maximally localized orbitals overlapping sites, respectively. This approach reveals that oxaquinuclidine ring steric hindrance and the electron densities throughout the molecules. Density function theory (DFT) provides more evidence for the ring's orientation and the molecules' reactivity. A molecular docking investigation of four essential COVID-19 proteins was carried out using these theoretical ideas. This investigation demonstrates that each protein's reactivity varies; certain proteins have more interaction with high electron density molecules (electron-donating substituent), while others have more interaction with low electron density molecules (electron-withdrawing substituent). The ADMET and drug-likeness investigations reveal that methoxy group substituted molecules perfectly correlate with the required pharmacological characteristics. The cytotoxicity of the five compounds was assessed using the HEK293T cell.

Optimizing Coreopsis tinctoria Flower Extraction and Inhibiting CML Activity: Box-Behnken Design.

Chronic myelogenous leukemia (CML) is an uncommon type of cancer of the bone marrow associated with high mortality. Although several effective therapies have been developed to reduce symptoms in patients with CML, many of these methods are associated with side effects. Coreopsis tinctoria Nutt. (C. tinctoria) is a natural medicinal material that possesses antioxidant and anticancer activities. Yet, its effect in treating leukemia has still not been fully explored. To optimize the C. tinctoria flower extraction process and investigate whether these extracts can impair CML cell survival. The extraction process of C. tinctoria was optimized by the Box-Behnken design response surface method. K562 cells were treated with different volumes (0, 10, 25, 50, and 100 μL) of C. tinctoria flower extracts. The effect of C. tinctoria extract on cell morphology and cell apoptosis was assessed by light microscopy, laser confocal microscopy, and flow cytometry. We established the following optimized C. tinctoria flower extraction conditions: temperature of 84.4°C, extraction period of 10 mins, solid-liquid ratio of 1:65, and times 4. These conditions were applied for C. tinctoria flower extraction. Pre-incubation of extracts prepared under the aforementioned optimal conditions with K562 cells induced cell cytotoxicity and cell apoptosis. C. tinctoria flower extracts exert obvious anti-leukemia effects in vitro and may be a potential drug candidate for leukemia treatment.

Amitriptyline protects afferent synapses in the cochlea against excitotoxic trauma in vitro.

Afferent synapses between inner hair cells (IHCs) and the type I spiral ganglion neurons (SGNs) in the cochlea provide over 95% of sensory signals for auditory perception in the brain. However, these afferent synapses are particularly vulnerable to damage, for example from excitotoxicity, and exposure to noise in the environment which often leads to noise-induced cochlear synaptopathy (NICS). In this study, we simulated excitotoxic trauma by incubating kainic acid, a non-desensitizing agonist for AMPA type glutamate receptors on cultured cochleae. The possible protective effects of amitriptyline against NICS were examined. We found that, in IHCs, amitriptyline reversed the decrease of Ca2+ current and exocytosis caused by excitotoxic trauma. In SGNs, amitriptyline promoted the recovery of neurite loss caused by excitotoxic trauma. Furthermore, we found that the protective effects of amitriptyline are likely mediated by suppressing apoptosis factors that were upregulated during excitotoxic trauma. In conclusion, our results suggest that amitriptyline could protect afferent synapses in the cochlea from NICS, making it a potential drug candidate for hearing protection.