Good Binding Affinity Research Articles

Comparative study of essential oil extraction from lime peel (Citrus amblycarpa Hassk. Ochse): Impact on chemical composition and bioactivities of anti-tyrosinase, anti-elastase, and antimicrobial properties

Essential oil is a natural substance widely utilized in the cosmetics industry. However, there has been no study on the cosmetic bioactivity of essential oil from the peel of Citrus amblycarpa Hassk. Ochse (CAEO). This study aimed to investigate the potential of CAEO, obtained through NaCl hydrodistillation (HD) and microwave-assisted hydrodistillation (MAHD), as an anti-tyrosinase, anti-elastase, and antibacterial agent, along with analyzing its chemical constituents. GC-MS analysis identified β-pinene (28.3%) and limonene (27.1%) as the main compounds in CAEO (HD), while limonene (13.75%) and citronellal (7.49%) predominated in CAEO (MAHD). The CAEO obtained from HD with 25% NaCl as the solvent exhibited significantly higher (p < 0.05) anti-tyrosinase (IC50 = 235.94 ± 1.34 μg/mL) and anti-elastase (IC50 = 41.59 ± 0.47 μg/mL) activities compared to the CAEO from the MAHD method. This result was consistent with the in silico pharmacological study, which revealed that limonene, the major component of CAEO, showed good binding affinity to the active sites of elastase and tyrosinase. The CAEO obtained from both methods exhibited strong and selective antibacterial activity in a disc diffusion assay against two bacteria associated with skin acne: Propionibacterium acnes ATCC 11827 (CAEO HD = 24.08 ± 5.85 mm) and Staphylococcus aureus ATCC 25923 (CAEO MAHD = 20.5 ± 0.27 mm). These results pave the way for further studies on the bioassay-guided isolation of CAEO to enhance its effectiveness as a cosmetic agent. Moreover, this study provides the first report indicating the potential of CAEO for development as a cosmetic agent.

Phytotoxic impact of di-butyl phthalate (DBP) on physiological, biochemical, and oxidative stress parameters of rice (Oryza sativa).

Phthalates are synthetic compounds, well-known plasticizers, with numerous applications and reported to have adverse effects on all living organisms residing in terrestrial and aquatic environments. In this study, the rice (Oryza sativa) seedlings were exposed to di-butyl phthalate (DBP) exogenously for 7days, with varying concentrations of 0, 200, 400, 800, and 1600mg/L, to explore the toxicological, physiological, and biochemical consequences by measuring various parameters such as pigment, lipid, and H2O2 (hydrogen peroxide) contents. The biochemical analysis of seedlings showed that the pigments, lipids, and H2O2 concentrations were altered abnormally. After 7days of exposure, the maximum amount of DBP was accumulated and translocated in both the shoot and root of the grown seedlings, and all morphological parameters (i.e., length and weight of both shoot and root) and pigment content (such as total carotenoid, chlorophyll a and b) were declined significantly. Superoxide dismutase (SOD), H2O2, and thiobarbituric acid reactive substance (TBARS) levels in seedlings increase as the stress increases due to the higher exposure dose of DBP. Cell viability was observed under a confocal microscope confirming the damage of the plasma membrane. Additionally, molecular docking studies indicated that DBP has a good binding affinity with key antioxidant enzymes of Oryza sativa, interacting via hydrogen bonds with specific amino acids. This suggests a potential mechanistic pathway for the observed biochemical changes in Oryza sativa.

Synthesis, antibacterial and anticancer activity of azo-based and aminomethylene derivatives of cyclic β-keto sulfones.

Herein we describe efficient and cost-effective synthesis of azo-based and aminomethylene derivatives of cyclic β-keto sulfones, specifically, 4,4-disubstituted (E)-2-(2-phenylhydrazineylidene)dihydrothiophen-3(2H)-one 1,1-dioxides and 4,4-disubstituted (E)-2-((methylamino)methylene)dihydrothiophen-3(2H)-one 1,1-dioxides. The azo-based derivatives were prepared through the azo coupling of cyclic β-keto sulfones with aromatic diazonium acetates, in situ prepared by diazotization of appropriate substituted amino benzenes. The aminomethylene derivatives were synthesized through the condensation of cyclic β-keto sulfones with DMF-DMA followed by a transamination reaction with primary amines. The target products were obtained in good yields and their structure was unambiguously established based on NMR spectra data, X-ray diffraction study, and DFT calculations. These compounds were designed as cost-effective and multitarget biologically active compounds. Further in vitro study showed antibacterial activity against Staphylococcus aureus and cytotoxicity against the MDA-MB-231 breast cancer cell line without affecting non-malignant cells MAEC. The molecular docking study confirmed good binding affinity of the studied compounds for DHPS, crucial for the bacterial life cycle and for CLK4 and IDO1, which are the therapeutic targets in cancer treatment.

Synthesis and Anticancer Activity Evaluation of N-(3,4,5- Trimethoxycinnamoyl)anthranilic Acid Derivatives

There is an urgent need to search for more efficient, better-tolerated anticancer drugs. Tranilast, a synthetic analog of tryptophan metabolite, has been shown to inhibit the growth of various cancer cells. In our previous study, the tranilast analog TRA01 [N-(3,4,5- trimethoxycinnamoyl)anthranilic acid] was identified as a promising agent against the proliferation of MCF-7 and HepG2 cell lines along with good binding affinity on the transforming growth factor beta 1 (TGFβ1) target. To further explore the structure-activity relationship, a series of N-(3,4,5- trimethoxycinnamoyl)anthranilic acid derivatives (5a–i) were successfully synthesized via a two-step synthetic procedure based on N-acylation and Knoevenagel-Doebner reactions and their structures were determined using 1 H-NMR, 13C-NMR, and MS spectra. The derivatives (5a–i) were evaluated for in vitro activity using MTT assay and in silico docking on TGFβ1 target by AutoDockTools–1.5.6 software. The bioactivity results of 5a–i showed 12.30–27.04% and 19.13–46.23% inhibition on proliferation of MCF-7 and HepG2 cell lines at 100 µM concentration, respectively, with the fluorinated derivatives (5a and 5e) possessing the strongest inhibitory activities. The molecular docking also found the best binding affinity of 5a (-8.70 Kcal/mol) and 5e (-8.71 Kcal/mol) on the TGFβ1 target. The SAR result revealed that substituents on the benzene ring of anthranilic acid were not favored for anticancer activity. Although these derivatives exhibited weak anticancer properties, the good binding affinity to the TGFβ1 target suggested certain potential of this scaffold for further study on this target.

Evaluating the potential of Kalanchoe pinnata, Piper amalago amalago, and other botanicals as economical insecticidal synergists against Anopheles gambiae

BackgroundSynergists reduce insecticide metabolism in mosquitoes by competing with insecticides for the active sites of metabolic enzymes, such as cytochrome P450s (CYPs). This increases the availability of the insecticide at its specific target site. The combination of both insecticides and synergists increases the toxicity of the mixture. Given the demonstrated resistance to the classical insecticides in numerous Anopheles spp., the use of synergists is becoming increasingly pertinent. Tropical plants synthesize diverse phytochemicals, presenting a repository of potential synergists.MethodsExtracts prepared from medicinal plants found in Jamaica were screened against recombinant Anopheles gambiae CYP6M2 and CYP6P3, and Anopheles funestus CYP6P9a, CYPs associated with anopheline resistance to pyrethroids and several other insecticide classes. The toxicity of these extracts alone or as synergists, was evaluated using bottle bioassays with the insecticide permethrin. RNA sequencing and in silico modelling were used to determine the mode of action of the extracts.ResultsAqueous extracts of Piper amalago var. amalago inhibited CYP6P9a, CYP6M2, and CYP6P3 with IC50s of 2.61 ± 0.17, 4.3 ± 0.42, and 5.84 ± 0.42 μg/ml, respectively, while extracts of Kalanchoe pinnata, inhibited CYP6M2 with an IC50 of 3.52 ± 0.68 μg/ml. Ethanol extracts of P. amalago var. amalago and K. pinnata displayed dose-dependent insecticidal activity against An. gambiae, with LD50s of 368.42 and 282.37 ng/mosquito, respectively. Additionally, An. gambiae pretreated with K. pinnata (dose: 1.43 μg/mosquito) demonstrated increased susceptibility (83.19 ± 6.14%) to permethrin in a bottle bioassay at 30 min compared to the permethrin only treatment (0% mortality). RNA sequencing demonstrated gene modulation for CYP genes in anopheline mosquitoes exposed to 715 ng of ethanolic plant extract at 24 h. In silico modelling showed good binding affinity between CYPs and the plants’ secondary metabolites.ConclusionThis study demonstrates that extracts from P. amalago var. amalago and K. pinnata, with inhibitory properties, IC50 < 6.95 μg/ml, against recombinant anopheline CYPs may be developed as natural synergists against anopheline mosquitoes. Novel synergists can help to overcome metabolic resistance to insecticides, which is increasingly reported in malaria vectors.Graphical

Dapagliflozin attenuates skeletal muscle atrophy in diabetic nephropathy mice through suppressing Gasdermin D-mediated pyroptosis.

Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear. The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits. Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin. Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.

Phytochemical profiling, spectroscopic identification of active compounds, and mechanism of the anticandidal properties of Datura stramonium L. using SwissADMET prediction and molecular docking analysis

BackgroundDatura stramonium L., a wild-growing herb, has been traditionally used to treat various ailments, including toothache, asthma, rheumatism, epilepsy, and alopecia. Scientific evidence supports its anticancer, anti-inflammatory, anti-asthmatic, anticholinergic, antifungal, and antibacterial properties. AimThis study aimed to isolate, characterize, and identify the most potent anticandidal compounds inhibiting the growth of Candida spp., while also predicting their drug-likeness and toxicity profiles. MethodThe anticandidal activity of D. stramonium leaf extracts was assessed using the Agar well-diffusion method and minimum inhibitory concentration (MIC) was determined by the broth dilution method. The most active extract was selected for column chromatography. Different fractions were collected and screened against pathogenic Candida spp. The most active fraction was subjected to Gas chromatography-Mass spectrometry (GC-MS), Fourier Transform-Infrared Spectroscopy (FT-IR), and Nuclear Magnetic Resonance (NMR) analysis. Additionally, computational tools such as molecular docking and ADMET prediction provided further insights into the molecular interactions between the target enzymes. ResultsIn vitro anticandidal activity demonstrated that the ethyl acetate extract exhibited significant activity against human pathogenic Candida spp., with the highest zones of inhibition against Candida guilliermondii (20.33±0.56 mm), Candida tropicalis (16.33±0.58 mm), and Candida albicans (14.66±1.05 mm), with a minimum inhibitory concentration (MIC) value of 25 ug/ml. Additionally, the most potent fraction (F8) obtained from the Column revealed significant anticandidal activity. GC-MS analysis of the F8 fraction indicated the presence of 23 compounds, with the major compounds being Phthalic acid, di(2-propylpentyl) ester (Compound 1), Pentadecane (Compound 2), Octadecane (Compound 3), Benzoic acid, 3-Amino-5-Hydroxy-, Methyl ester (Compound 4), and 1,2-Benzenedicarboxylic acid, bis (2-ethylhexyl) ester (Compound 5). This study reports all 23 compounds from D. stramonium for the first time. Furthermore, NMR studies confirmed the presence of Phthalic acid, di(2-propylpentyl) ester as the most abundant compound, designated as compound 1. Finally, docking analysis revealed that compound 1 showed good binding affinities for the tested enzymes, with the highest binding scores of -7.084 Kcal/mol and -7.030 Kcal/mol with Lanosterol 14-alpha demethylase (PDB ID: 5JLC, 5TZ1). The results of the in silico pharmacokinetic and drug-likeness properties indicated that compound 1 is a potential anticandidal drug candidate. ConclusionThis study highlights that 23 compounds were reported from the leaf extract of D. stramonium for the first time. The findings suggest that compound 1 can be considered a new anticandidal drug candidate.

Synthesis, characterization and biological profile of some new dihydropyrimidinone derivaties.

The rise of drug-resistant bacteria, viruses, and fungi has prompted the search for new drugs without cross-resistance to current treatments. As a result, the aim of this research was to synthesize various types of dihydropyrimidinones heterocyclic compounds and screened them for their antibiotic properties. Newly synthesized dihydropyrimidinone derivatives were characterized spectroscopically using proton NMR (1HNMR), and FT-IR. These substances were then subjected to molecular docking studies via Auto dock Vina software to determine their affinity for binding to proteins from different bacterial strains including (Staphylococcus epidermidis (S. epidermidis), Staphylococcus aureus (S. aureus), Mycobacterium luteus (M. luteus), Salmonella typhi (S.typhi), Bacillus subtilis (B. subtilis), and Escherichia coli (E. coli) and fungal (Candida glabrata (C. glabrata), Candida albicans (C. albicans), and Saccharomyces cerevisiae (S. cerevisiae) strains. Also in-vitro anti-fungal, anti-bacterial and anti-oxidant activity was performed by using ager well diffusion method and DPPH assay respectively. Moreover, the In-vivo biological evaluation of these derivatives was conducted by using carrageenan-induced hind paw model. The cytotoxicity profile of the synthesized derivatives was done via in-vitro MTT assay. All newly synthesized derivatives were confirmed via the multiple spectroscopic analysis techniques. All derivatives showed good binding affinities against the multiple targeted protein with. Compound 4c exhibited hightest potential with -10kcal/mol against bacterial strains. 4b showed best antifungal potential with -10.8kcal/mol binding affinities. For Bacillus subtilis compound 4b and 4c performed best with 17mm±2.21. for anti-fungal activity against Candida glabrata, amongst the five newly formed compounds, 4a showed best activity with 19mm±1.22 The analogue 4b exhibited best anti-oxidant potential with 63.85±1.39. Compound 4a and 4b showed highest anti-inflammatory potential with 1.011mm±0.247mg/kg and 1.447±0.212mg/kg in countering inflammation by targeting toll-like receptor activation and reduce the inflammation in hind paw edema. The selected derivatives exhibited no toxicity profile with 99 % and 98 % cell survival rate using compound 4a and 4b. Research has been done on the multiple biological activities of dihydropyrimidinones derivatives but the innovation on MDR is still pending. New dihydropyrimidinone derivatives were developed as agents to combat drug resistance. The results of these studies showed that newly synthesized dihydropyrimidinone derivatives are remarkably effective not only as anti-biotic agents but also counter inflammation caused by carrageenan resulting from the activation of the Toll-like receptors (TLRs) signaling pathway along with the non-toxic effect. So it is concluded that the recently synthesized new dihyropyrimidinone derivatives are highly effective antimicrobial derivatives with non-toxic effects on human cell lines.

SQYC formula improves the efficacy of PD-1 monoclonal antibodies in MSS colorectal cancer by regulating dendritic cell mitophagy via the PINK1-Parkin pathway.

Microsatellite stable (MSS) colorectal carcinomas (CRCs) exhibit poor responsiveness to immunotherapy such as immune checkpoint inhibitors (ICIs). In the realm of clinical cancer treatment, traditional Chinese medicines (TCMs) are extensively utilized for their immunomodulatory properties. Shen Qi Yi Chang (SQYC), a clinical prescription for CRC treatment, improve the life quality of CRC patients and enhance their immune function. This study was to reveal the effect and mechanism of SQYC in improving the effect of PD-1 inhibitors in the treatment of MSS-type CRC. CT26-luc in situ CRC tumor model and human CRC organoid model was established to evaluate the anti-tumor efficacy of SQYC combined with PD-1 inhibitor. Flow cytometry analysis was utilized to investigate the effect of SQYC on the infiltration and immune function of TILs and DCs in the immune microenvironment. Following this, RNA sequencing analysis, seahorse, TEM and immunofluorescence were performed to regulation of SQYC on mitophagy in DCs cells. UPLC-Q-TOF/MS and molecular docking were used to reveal the key blood-entering components of SQYC-regulated PINK1-parkin pathway. The SQYC-containing serum improved the efficacy of sintilimab in MSS CRC organoid model. After combined administration of 11.4 g/kg/day SQYC extract and 5 mg/kg α-PD-1, it was observed that SQYC enhanced the efficacy of PD-1 inhibitor against MSS CRC. Flow cytometry and immunofluorescence analysis revealed an augmented infiltration of tumor-infiltrating lymphocytes (TILs) and an improved antigen presentation function of dendritic cells (DCs). Notably, RNA sequencing analysis demonstrated an evident correlation with mitochondrial function related pathways following SQYC treatment. Mechanistically, SQYC promoted mitophagy in DCs via the PINK1-Parkin pathway, thereby improving mitochondrial quality, energy metabolism, and mitochondrial dynamics. Evaluation of the blood components of SQYC coupled with molecular docking, demonstrated good binding affinity with PINK1/PARKIN/LC3. Our findings highlight SQYC as a promising candidate for improving immunotherapy in MSS CRC, suggesting that targeting PINK1-Parkin in DCs could represent a novel strategy for improving the efficacy of ICIs. Furthermore, it provides new theoretical and scientific underpinnings to enhance the clinical efficacy of immunosuppressants.

Identification of lipid metabolism-related gene markers and construction of a diagnostic model for multiple sclerosis: An integrated analysis by bioinformatics and machine learning.

Multiple sclerosis (MS) is an autoimmune inflammatory disorder that causes neurological disability. Dysregulated lipid metabolism contributes to the pathogenesis of MS. This study aimed to identify lipid metabolism-related gene markers and construct a diagnostic model for MS. Gene expression profiles for MS were obtained from the Gene Expression Omnibus database. Differentially expressed lipid metabolism-related genes (LMRGs) were identified and performed functional enrichment analysis. Least absolute shrinkage and selection operator (LASSO), random forest (RF), and protein-protein interaction (PPI) analysis were employed to screen hub genes. The predictive power of hub genes was evaluated using receiver operating characteristic (ROC) curves. We developed an artificial neural network (ANN) model and validated its performance in three test sets. Immune cell infiltration analysis, Gene set enrichment analysis, and ceRNA network construction were performed to explore the role of lipid metabolism in the pathogenesis of MS. Drugs prediction and molecular docking were utilized to identify potential therapeutic drugs. We identified 40 differentially expressed LMRGs, with significant enrichment in Arachidonic acid metabolism, Steroid hormone biosynthesis, Fatty acid elongation, and Sphingolipid metabolism. AKR1C3, NFKB1, and ABCA1 were identified as gene markers for MS, and their expression was upregulated in the MS group. The areas under the ROC curve (AUCs) for AKR1C3, NFKB1, and ABCA1 in the training set were 0.779, 0.703, and 0.726, respectively. The ANN model exhibited good discriminative ability in both the training and test sets, achieving an AUC of 0.826 on the training set and AUC values of 0.822, 0.890, and 0.833 on the test sets. Gamma.delta.T.cell, Natural.killer.T.cell, Plasmacytoid.dendritic.cell, Regulatory.T.cell, and Type.1.T.helper.cell were highly expressed in the MS group. A ceRNA network showed a complex regulatory interplay involving hub genes. Luteolin, isoflavone, and thalidomide had good binding affinities to the hub genes. Our study emphasized the crucial role of lipid metabolism in MS, identifing AKR1C3, NFKB1, and ABCA1 as gene markers. The ANN model exhibited good performance on both the training and testing sets. These findings offer valuable insights into the molecular mechanisms underlying MS, and establish a scientific foundation for future research.

Design, Synthesis, Cytotoxicity Profiling, Molecular Docking and ADMET Studies of Novel Functionalized Coumarin-pyrazole-thiazole Hybrids: Cyclization of Chromonyl Thiazolyl Pyrazolyl Thiosemicarbazone with α-Halocarbonyl Reagents

: A simple synthetic method was performed to design a novel series of polycyclic systems consisting of a coumarin-pyrazole-thiazole skeleton linked with a completed thiazole ring via hydrazone linkage. The methodology depended on the cyclization of the active precursor 2-[(3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazol-4-yl)methylene] hydrazine-1-carbothioamide (2) by its reaction with a series of α-halocarbonyl reagents under Hantzsch reaction conditions. The spectral and analytical data confirmed the structures of all the synthesized compounds. The target compounds were screened for their in vitro anticancer activity. The cytotoxic effects of obtained compound were screened against cancer cell lines (MCF-7, HepG2, and HCT116) using the standard SRB method. Furthermore, products 4, 5, and 7b were the most active against all cancer cell lines, compared with Doxorubicin. These bioactive products effectively suppress the growth of cancer cells by activating the cell death program through late apoptosis. In addition, products 4 and 5 arrested the cell cycle at the S and G2 phases, while product 7b has the ability to arrest the cell cycle at the G2 phase against all three cancer cells. The molecular docking of the products 4, 5, and 7b showed good binding affinities with Cyclin-dependent kinase 8 (CDK-8), while the ADMET prediction supported that these bioactive products can be promising anticancer agents.

Discovery of new benzothiazole-1,2,3-triazole hybrid-based hydrazone/thiosemicarbazone derivatives as potent EGFR inhibitors with cytotoxicity against cancer.

Considering the widespread availability of certain medicines, there is still a critical need for potent anti-cancer agents. It is owing to numerous negative impacts and non-functionality of current drugs, particularly during the late stages of illness. To accomplish this, the new array of 1,2,3-triazole-benzothiazole molecular conjugates tethering hydrazone/thiosemicarbazone linkage 8a-l have been successfully synthesized via the efficient copper-catalyzed 1,3-dipolar cycloaddition of the appropriate un/substituted benzothiazole azides 4a-c with several O-propargylated benzylidene derivatives 7a-d. The newly established 1,2,3-triazole structural hybrids were thoroughly characterized using appropriate spectroscopic techniques (IR, 1H, 13C-NMR & CHN analysis). The cytotoxic features of the investigated triazole hybrids were assessed against three human cancer cell lines, A549, T47-D, and HCT-116 cancer cells, using the MTT assay. Based on the findings, the breast cancer cell line T47D displayed promising results with IC50 values of 13, 17, and 19 μM for the synthesized molecules 8a-c, respectively. Furthermore, the safety assessment of these compounds on normal cell lines revealed a relatively low risk to normal cells, as indicated by their IC50 values exceeding 500 μM, suggesting a reasonable safety margin. Interestingly, the most relevant derivatives 8a, 8b, and 8c, exhibited IC50 values of 0.69, 1.16, and 4.82 μM, respectively, causing inhibition of 98.5%, 96.8%, and 92.3%, compared to Erlotinib (IC50 = 1.3 μM, 98.2% inhibition). Molecular docking results exhibited a good binding affinity of compounds 8a and 8b towards the EGFR active site. Accordingly, these compounds can be further developed as target-oriented EGFR chemotherapeutics against cancer.

Identification and validation of WDR5 WIN-site ligands via DNA-encoded chemical library screening

WD repeat-containing protein 5 (WDR5) is a scaffolding protein involved in critical protein–protein interactions and a promising target for therapeutic development. Novel small-molecule ligands targeting WDR5 were identified using the DELopen platform, a free-access DNA-encoded chemical library (DEL) for academic research. Through off-DNA structure–activity relationship studies and photoaffinity labeling, two promising initial leads, DBL-6-13 and DBL-6-33, were identified as new binders of WDR5. These compounds exhibited moderate to good binding affinities and were confirmed to bind the WIN-site through co-crystal structure analysis. Our findings demonstrate the utility of DEL technology in identifying ligands for challenging targets like WDR5, particularly within an academic research setting using the DELopen platform. The identified WDR5 ligands offer a foundation for further optimization and exploration as chemical probes for WDR5 research.

Exploring 1,2,3-triazole-Schiff's base hybrids as innovative EGFR inhibitors for the treatment of breast cancer: In vitro and in silico study.

EGFR inhibitors are a class of targeted therapies utilized in the management of certain tumor kinds such as NSCLC and breast cancer. Series of 1,2,3-triazole-Schiff's base hybrids were designed, synthesized, and estimated for their antitumor effect toward breast cancer cells, MCF-7 and MDA-MB-231. The safety and selectivity of the new compounds were tested using normal cell (WI-38). Analogs 4a, 4b, and 5f demonstrated significant antitumor effects toward both MCF-7 and MDA-MB-231 with IC50 range of 5.61-18.01µM in comparison to Doxorubicin (6.72µM). Moreover, they proved considerable selectivity toward the tested cancer cells (SI values of 4.36-5.33). The superior compounds were investigated for EGFR inhibition where compounds 4b and 5f showed the highest EGFR inhibition effect with IC50 equal 0.16 and 0.15µM, respectively utilizing Gefitinib as reference (IC50=0.081µM). Further mechanistic studies for hybrid 5f in MDA-MB-231 cells, exhibited cell cycle arrest at G2/M phase by 29.85% that was accompanied by the elevation of apoptosis percent by 48-fold more than the control. The apoptosis studies indicated that hybrid 5f was able to upregulate Bax (9.43 folds) while downregulate Bcl-2 (0.27) with substantial remarkable elevation of Bax/Bcl-2 ratio (35:1). Furthermore, it upregulated both caspases 8 and 9 by 2.93 and 6.54-fold, respectively. Molecular modeling studies showed the good binding affinity of compounds 4b and 5f with EGFR kinase active site explaining their potent biological effects. Drug likeness and ADMET features of compounds 4b and 5f demonstrated that they represent promising drug like candidates against breast cancer.

Uncovering the Natural Inhibitors From Medicinal Plants to Alleviate Human Cancers Targeting the p53 Protein: An In Silico Approach

AbstractThe tumor suppressor p53 protein plays a key role in controlling several essential cellular responses, including cell growth, development, and apoptosis, helping to prevent cancer development. In various cancers, loss of p53 function results in prolonged cell replication and inhibition of programmed cell death. There are a few options available to target p53, but they come with limitations. For this reason, there is a need for novel drug candidates to maintain p53 functionality. Therefore, our study aims to identify potential natural bioactive compounds through comprehensive in silico methods such as molecular docking, MM/GBSA (molecular mechanics generalized born surface area), ADME/T (absorption, distribution, metabolism, excretion, and toxicity), and molecular dynamics (MD) simulation against the targeted protein p53. Initially, 462 phytochemicals from 23 medicinal plants were screened using molecular docking and MM‐GBSA studies to find potential phytochemicals. From the studies, the top three compounds, CID‐3469, CID‐5280372, and CID‐591524, were selected based on their good binding affinities for further investigation, where all the compounds showed better drug‐likeness with no toxicity in ADME/T analysis. MD simulation depicted better structural stability of phytocompounds in complexes with p53 protein. This study shows novel insights into the development of novel bioactive compounds as drug candidates for cancer treatment.

In-silico ADMET and molecular docking evaluation of an active cyclopeptide from a Saharan Streptomyces strain with anticancer, anti-HIV, and anti- SARS-CoV-2 activities

The emergence of new SARS-CoV-2 variants, HIV drug resistance, and the persistent burden of breast cancer have created an urgent need to identify new antiviral and anticancer drug candidates. In this investigation, we employed in-silico methods to evaluate the pharmacokinetic proprieties and toxicity, and the inhibitory potential of a cyclic peptide compound produced by a novel Streptomyces strain using target enzymes. In silico analysis of the ADMET profile indicates that the cyclic peptide cyclo(L-pro-L-tyr) has favorable physicochemical properties, good lipophilicity and water solubility, generally favorable pharmacokinetic characteristics, and low toxicity for the cyclic peptide. In addition, the docking studies of the compound showed strong binding affinities with HIV-1 integrase at -7.4 kcal/mol, HIV-1 reverse transcriptase at -8.1 kcal/mol, COVID-19 main protease at -8.5 kcal/mol, and SARS-CoV-2 spike glycoprotein at -7.7 kcal/mol compared to references inhibitors. Furthermore, it has a good binding affinity with estrogen receptor alpha associated with breast cancer at -6.8 kcal/mol compared to reference inhibitors. Therefore, the findings demonstrate the potential of cyclo(L-pro-L-tyr) as a novel bioactive compound with antiviral and anticancer properties. This means that it needs to be tested in more experiments and further developed as a lead compound for treating SARS-CoV-2 infections, HIV/AIDS, and breast cancer.

Molecular docking and invitro evaluation of glucosamine sulfate targeting MMP-3, MMP-9, and IL-4 for potential osteoarthritis treatment.

This study intended to investigate the potential of glucosamine sulfate (GS) as an inhibitor of genes involved in osteoarthritis (OA) development. Despite GS is often used for OA treatment due to its cartilage preservation and minimum side effects, the molecular mechanism behind its interactions remains unknown. Molecular docking was conducted to analyze the interactions between glucosamine sulfate and genes associated with OA such as matrix metalloproteinase-3 (MMP-3), MMP-9, and interleukin-4 (IL-4). Additionally, a cell viability assay using RAW 264.7 cells was performed to evaluate the toxicity of glucosamine sulfate at various concentrations. Molecular docking results revealed that glucosamine sulfate has a good binding affinity and stable interactions with MMP-3, MMP-9, and IL-4, indicating that it may have inhibitory effects on targeted genes. Nevertheless, the cell viability assay analysis demonstrated that glucosamine sulfate had considerable toxic effects in RAW 264.7 cells at highest concentrations. Glucosamine sulfate exhibited stable molecular interactions with genes associated to OA development. However, GS toxicity at high concentrations necessitates future research studies to optimize dosing and assess its therapeutic safety in OA treatment.

Network pharmacology integrated with molecular docking and molecular dynamics simulations to explore the mechanism of Shaoyao Gancao Tang in the treatment of asthma and irritable bowel syndrome.

Numerous studies have demonstrated a correlation between asthma and irritable bowel syndrome (IBS). The Chinese herbal compound Shaoyao Gancao Tang (SYGCT) has been found to have therapeutic effects on both asthma and IBS, but the underlying mechanisms are not yet fully understood. This study aims to explore the key components, key targets, and potential mechanisms of SYGCT in treating asthma with IBS by using network pharmacology, molecular docking techniques and molecular dynamics simulation. The major chemical components and potential target genes of SYGCT were screened by bioinformatics. The key targets of Asthma-IBS comorbidity were identified based on network modules. The intersection of the drug targets and disease targets was identified as the potential targets of SYGCT in treating asthma-IBS. Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to identify the biological processes and signaling pathways involved in these potential targets. A protein-protein interaction network was constructed to identify hub targets, while a drug-compound-target topological network was built to screen key compounds. Molecular docking was used to verify the affinity between the hub targets and key compounds. Molecular dynamics analysis was utilized to assess the binding stability of these interactions. Network pharmacology analysis revealed that the therapeutic effect of SYGCT on asthma-IBS involved multiple biological processes and signaling pathways. It may exert therapeutic effects primarily through signaling pathways such as IL-17, TNF, and Th17 cell differentiation. The possible targets of SYGCT in the treatment of asthma-IBS could be IL6, TNF, JUN, PTGS2, STAT3, IL1B, CASP3, NFKBIA, IL10, and PPARG. Molecular docking verification showed that the predicted targets had good binding affinity with the compounds, among which PTGS2, CASP3, and PPARG had higher binding energy. Molecular dynamics simulation revealed that PTGS2, CASP3, and PPARG proteins had good stability and high binding strength with the compounds 2-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenol and shinpterocarpin. SYGCT plays a therapeutic role in asthma and IBS through multiple targets and pathways, providing a theoretical basis for explaining the mechanism and clinical application of SYGCT in treating different diseases with the same treatment in asthma and IBS.

Encoding Anticancer Potential of Zingerone: Bioinformatic and Molecular Docking Analysis Targeting Liver Cancer

Liver cancer is the third-leading cause of cancer death globally, requiring research on molecular mechanisms for sustainable prevention and treatment. With expensive conventional drugs and severe side effects, novel medications are needed. Therefore, in the current investigation employing a bioinformatic approach, we explored the bioactive phytocompound zingerone for its anticancer efficacy targeting liver cancer. The study analyzed phytocompounds’ drug-like nature using SWISS ADME, finding them orally available and meeting Lipinski, Ghose, Veber, Egan, and Muegge rules. They showed good ADMET properties and strong interactions with apoptotic regulator target proteins, making them safe for commercial anticancer drugs. hGLUT, DDEFL1, HBx, BCl2 , AFP, NF kappa, and Heat Shock Protein 70 Shows good binding affinity in the range of -5.3 to -6.0 kcal/mol. The phytocompound zingerone shows good binding affinity with all target proteins (-5.8 to -6.0 kcal/mol), thereby possessing appreciable bonded and non-bonded interactions with the binding pockets of target proteins. This study’s findings could lead to the development of promising drug candidates for liver cancer, laying the foundation for the development of novel anticancer therapeutics.

Liang-Ge-San Decoction Ameliorates Acute Respiratory Distress Syndrome via Suppressing p38MAPK-NF-κ B Signaling Pathway.

To explore the potential effects and mechanisms of Liang-Ge-San (LGS) for the treatment of acute respiratory distress syndrome (ARDS) through network pharmacology analysis and to verify LGS activity through biological experiments. The key ingredients of LGS and related targets were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. ARDS-related targets were selected from GeneCards and DisGeNET databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using the Metascape Database. Molecular docking analysis was used to confirm the binding affinity of the core compounds with key therapeutic targets. Finally, the effects of LGS on key signaling pathways and biological processes were determined by in vitro and in vivo experiments. A total of LGS-related targets and 496 ARDS-related targets were obtained from the databases. Network pharmacological analysis suggested that LGS could treat ARDS based on the following information: LGS ingredients luteolin, wogonin, and baicalein may be potential candidate agents. Mitogen-activated protein kinase 14 (MAPK14), recombinant V-Rel reticuloendotheliosis viral oncogene homolog A (RELA), and tumor necrosis factor alpha (TNF-α) may be potential therapeutic targets. Reactive oxygen species metabolic process and the apoptotic signaling pathway were the main biological processes. The p38MAPK/NF-κ B signaling pathway might be the key signaling pathway activated by LGS against ARDS. Moreover, molecular docking demonstrated that luteolin, wogonin, and baicalein had a good binding affinity with MAPK14, RELA, and TNF α. In vitro experiments, LGS inhibited the expression and entry of p38 and p65 into the nucleation in human bronchial epithelial cells (HBE) cells induced by LPS, inhibited the inflammatory response and oxidative stress response, and inhibited HBE cell apoptosis (P<0.05 or P<0.01). In vivo experiments, LGS improved lung injury caused by ligation and puncture, reduced inflammatory responses, and inhibited the activation of p38MAPK and p65 (P<0.05 or P<0.01). LGS could reduce reactive oxygen species and inflammatory cytokine production by inhibiting p38MAPK/NF-κ B signaling pathway, thus reducing apoptosis and attenuating ARDS.