Molecular Docking Studies Research Articles

Abstract 4465: Molecular docking studies on the factors affecting histone deacetylase inhibition: Design, rigidity, and chirality of the inhibitors

Abstract Histone deacetylase (HDAC) has become one of the targets for cancer therapy since it was found overexpressed in cancer cells. New HDAC inhibitors were designed and investigated to demonstrate how the molecules interact with HDAC enzymes, using the molecular docking software ICM-Pro. Multiple families of HDAC inhibitors, derivatized from the FDA-approved HDAC inhibitors, were constructed and optimized for in silico screening. Detailed analyses of the docking results showed that the addition of an aromatic ring on the linker domain could boost or diminish the interactions of the molecules with the enzyme, depending on the location and size of the aromatic ring. The rigidity of the molecules was tuned by installing heterocyclic rings of various sizes at different positions. Molecules of specific rigidity could greatly enhance the dock scores and binding affinity, thus theoretically the enzyme inhibition. Modification of protein recognition and zinc-binding domains and chirality of the molecules were also explored to seek inhibitors for specific HDAC inhibitions. Drug candidates with the desired binding affinity and selectivity were selected for chemical synthesis and biological activity examination in the lab. Citation Format: Qinliang Zhao, Jacquelyn Ann Tang, Karina Artero, Audrey Huang, Rabeya Bosri. Molecular docking studies on the factors affecting histone deacetylase inhibition: Design, rigidity, and chirality of the inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4465.

Antiradical and anti-acethylcholinesterase constituents from the methylene chloride extract of Ganoderma applanatum (Pers.) Pat (Ganodermataceae) and molecular docking study.

Alzheimer's disease (AD) is a non-communicable disease with global impact. Inhibitors of acetylcholinesterase (AChE) are suitable therapies for AD. In this work, we report the isolation of antiacetylcholinesterase compounds from the methylene chloride (DCM) extract of the medical fungus Ganoderma applanatum (Pers.) Pat (Ganodermataceae). Chemical evaluation of this extract using chromatographic technics led to the isolation of a (1:1) mixture of ergosterol (1) and stellasterol (2), palmitic acid (3), ganodermanondiol (4), lucidumol B (5) and lupeol (6). Structures of these compounds were determined using spectroscopic analysis such as IR, MS, 1D & 2D NMR and literature. The acetylation reaction has been performed on the mixture (1 + 2) and compound 4, leading to the obtention the mixture of 3-acetyl-ergosterol (7) and 3-acetylstellasterol (8) along with 24-acetyl-ganodermanondiol (9) respectively. Total phenolic content was determined for DCM, Ethyl acetate and n-butanol extracts. To assess their antiradical scavenging potential, DPPH was used as free radical. The Inhibition power of acetylcholinesterase was evaluated in vitro using the Ellman reagent. Amongst all tested extracts, the DCM extract showed the high amount of total phenolic compounds with a value of 133.9512 mg EAG/g EX. The same extract showed a very good antiradical scavenging potential with an IC50 of 0.0021 mg/mL. The mixture (1 + 2) showed the highest antiradical scavenging activity with IC50 of 0.0770 mg/mL. The results obtained demonstrated that the acetylation has reduced the antiradical scavenging potential. Concerning the acetylcholinesterase inhibition power, the DCM extract and the mixture (1 + 2) showed a very good power with an inhibition percentage of 89%. The acetylation has also reduced the activity of the obtained derivative. The results provide insights into the potential efficacy of these compounds as acetylcholinesterase inhibitors. The binding interactions of the isolated and acetylated derivatives against acetylcholinesterase protein (PBP 3i6m) of Torpedo californica were studied using Autodock software. Ergosterol (-11.9 kcal/mol) binds better to the protein biding site through significant pi-sigma interactions.

Abstract 6533: Microbial metabolite ammonia disrupts CEACAM1 TGF-β signaling to drive colon cancer progression

Abstract Background: Colorectal cancer (CRC) is rising alarmingly in younger populations, potentially arising from additional risk factors such as obesity, pro-inflammatory microbiomes and accumulation of toxic metabolites. However, how metabolites such as ammonia impact key signaling pathways to promote CRC remains unclear. Our study investigates a critical link between gut microbiome alterations, ammonia, and their toxic effects on the TGF-β signaling pathway, to drive CRC progression. Methods: Through human TCGA-CRC data analyses, with animal model studies, molecular docking and signaling studies, we examine how gut microbiome alterations, particularly ammonia production, modulate key oncogenic pathways involving Smad3 adaptor, SPTBN1, CEACAM1, and TGF-β. Our work builds on two of our recent publications (Cell Rep.2024.43(9):114676 and Sci Transl Med.2021.13(624): eabk2267). Results We observe altered microbial populations in an obesity induced mouse model of cancer, where ammonia promotes caspase-3-mediated cleavage of the SMAD3 adaptor βII-spectrin (SPTBN1). Cleaved SPTBN1 fragments form adducts with ammonia that induce pro-inflammatory cytokine expression and disrupt TGF-β signaling. Extending on AlphaFold docking simulations, we identified that ammonia interacts with six polar residues at SPTBN1 (S553, Y556, S663, Y666, N986, and T1178) to form hydrogen bonds that disrupt downstream SMAD3 signaling, altering TGF-β signaling to a protumor genic phenotype. Blocking SPTBN1, through an SPTBN1-specific siRNA blocks ammonia toxicity and restores normal SMAD3/TGF-β signaling by reducing the abundance of SPTBN1-cleaved fragments in SW480 and HCT116 (CRC) cell lines. In addition, our research establishes crosstalk between TGF-β signaling and a microbial sensor, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is significantly overexpressed in CRC patients. We identified CEACAM1-SPTBN1 interactions at specific residues (E517 and Y520) within the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 cytoplasmic domain, identifying a potential axis that is harnessed by the altered microbiome. Conclusions: Our study identifies mechanistic insights into how microbial metabolites such as ammonia target TGF-β, a major signaling pathway, to promote CRC. These findings underscore the therapeutic potential of targeting SPTBN1 to restore tumor-suppressive TGF-β signaling and improve outcomes for CRC patients. Citation Format: Krishanu Bhowmick, Puja Ghosh, Xiyan Xiang, Xiaochun Yang, Taj Mohammad, Bibhuti Mishra, Md. Imtaiyaz Hassan, Adrian R Krainer, Srinivasan Dasarathy, Keith A Crandall, Lopa Mishra. Microbial metabolite ammonia disrupts CEACAM1 TGF-β signaling to drive colon cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6533.

Phytoconstituents from Artemisia annua medicinal plant as potent inhibitors targeting Salmonella SpvB: a molecular docking and dynamic study.

Salmonella, a genus with a global presence, is a leading cause of diarrheal diseases in both humans and animals. With over 2,400 distinct serotypes, most exhibiting minimal host specificity, Salmonella infection remains a significant public health issue. It poses a substantial economic burden on both developed and developing nations due to the costs associated with disease surveillance, prevention, and treatment. To address this global challenge, it is essential to explore cost-effective therapeutic interventions derived from medicinal plants. In this study, we targeted the Salmonella SpvB ATR domain for molecular docking of phytochemical compounds. A library of 392 phytochemical compounds from the Artemisia annua (Sweet wormwood) medicinal plant was utilized. In the initial screening, the top 20 phytochemical compounds were selected based on their high binding affinity toward SpvB. These 20 compounds underwent interaction analysis, revealing that two compounds, IMPHY004808 and IMPHY015047, formed crucial interactions. The IMPHY004808 compound bound at binding site residues ARG414, ARG471, LEU473, and GLU538, with residue SER501 present at the active site. Similarly, the IMPHY015047 compound formed bonds at binding site residues ARG471, ARG414, GLY472, and GLU538, while residue SER501 was present at the active site of SpvB. The trajectory analysis of 500 ns MD simulation, including deviation, fluctuation, compactness, surface area calculation, secondary structure element alterations, and hydrogen bond analysis, showed that the complexes were stable during the simulation time. Moreover, PCA with minimal vibration, FEL analysis and MMPBSA analysis strongly recommend that the complexes were stable and further validation with experimentation is needed.

Comparative chemical and antimicrobial evaluation of the essential oils from Callistemon and podocarpus species supported by in-silico molecular simulations against bacterial LacY protease

Abstract Background Myrtaceae and Podocarpaceae botanical families include several aromatic species that have been proven to have diverse pharmacological potential, especially antimicrobial effects. Additionally, plants of both families were reported for their benefits in traditional medicine. The current study demonstrated the chemical profile, antimicrobial of four investigated plant species (C. subulatus, C. rigidus, P. gracilior, and P. elongatus) leaves cultivated in the same place in Egypt and propose in-silico modeling for the antibacterial mechanistic action. Method The essential oils samples were prepared via hydrodistillation and headspace extraction protocol and GC analysis was conducted to obtain a comparative chemical profile. The antimicrobial activity of the obtained hydrodistillation essential oil samples was screened via agar diffusion, and the MIC was calculated via broth microdilution assays. An in silico molecular docking study was performed to investigate the inhibition of the LacY protease efflux pump. Results GC results revealed that the percentage of oxygenated monoterpenes was highest in the oil samples from Callistemon species (60.38 and 82.68%). In contrast, sesquiterpene hydrocarbons constituted the highest percentage of volatile classes in the oil samples from Podocarpus species (57.37 and 43.16%). C. rigidus-EO shows significant inhibitory activity against Gram-negative and Gram-positive pathogens, especially E. coli and S. viridans, with a calculated MIC of 0.878 ml, whereas P. elongatus EO shows notable activity against coagulase-negative Staphylococcus and the activity was comparable to that of the positive control antibiotics used (ciprofloxacin & doxycycline). Ultimately, an in silico molecular docking study on the binding site of the LacY protease enzyme revealed a significant binding affinity of the major docked volatile constituents. Conclusion The plant species investigated are considered a vital source of safe antimicrobial volatile constituents that are recommended as bioactive entities for controlling microbial infection topically or systemically. The proposed mechanistic action encourages further modification of the major EOs chemical structure by adding more polar substitutions to improve the binding affinity and produce more active semisynthetic analogues.

Green Synthesis of Pyrazole Linked Thiazole Derivatives with Enhanced Anti-Breast Cancer Activity: WEB-Mediated Protocol, Anticancer Screening, EGFR Inhibition, In Silico ADME and DFT Calculations.

The current research investigates the green and efficient water extract of banana peel (WEB) mediated synthesis of thiazole derivatives and their anticancer activity against the MCF-7 breast cancer cell line. A total ten novel thiazole derivatives were synthesized by green protocol and characterized by FT-IR, 1H NMR and 13C NMR spectroscopic methods confirming the successful synthesis of the desired thiazole derivatives. The synthesis protocol accommodates a range of aryl and halogen substitutions, allowing for flexibility in compound design and resulting in high yields (75-88%) across diverse derivatives. Compound 4e, bearing a methoxy group, emerged as the most potent candidate with an IC50 of 11.03 ± 1.047 µM, while compound 4c, featuring a chlorine substituent, also showed strong activity with an IC50 of 13.36 ± 1.21 µM. The structure-activity relationship (SAR) analysis indicated that both electron-donating and electron-withdrawing groups significantly influence anticancer potency. Molecular docking studies with EGFR revealed that compound 4e has the highest binding affinity, with a docking score of -6.98 kcal/mol, surpassing the standard drug Gefitinib (-6.45 kcal/mol). DFT study revealed electronic, chemical and biological characteristics of 4e through FMO, MESP and global descriptors. ADME analysis suggested favorable drug-like properties for most compounds.

New Amidino-Substituted Benzimidazole Derivatives as Human Dipeptidyl Peptidase III Inhibitors: Synthesis, In Vitro Evaluation, QSAR, and Molecular Docking Studies

Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that hydrolyses biologically active peptides by cleaving dipeptides from their amino terminus. While the fundamental role of this metallopeptidase remains incompletely understood, human DPP III (hDPP III) has been linked to several pathophysiological processes relevant to drug development. In this study, thirty-six amidino-substituted benzimidazole derivatives, including seven newly synthesized compounds, were examined for their activity against hDPP III by combining in vitro tests, in silico quantitative structure–activity relationship (QSAR) modelling, and molecular docking approaches. The experiments demonstrate that all compounds display inhibitory activity at a 30 µM concentration. A biochemical assay revealed that 2,2′-bithiophene, 4-trifluoromethylphenyl, 4-(N,N-diethylamino)phenyl, and 2,3,4-trihydroxyphenyl as substituents at position 2 of the benzimidazole core enhance inhibitor potency. Additionally, the type of substituent at positions 5(6) of the benzimidazole core influences enzyme inhibition, with effectiveness ranked as follows: 2-imidazolinyl > unsubstituted amidine > 2-tetrahydropyrimidine. A multiple linear regression QSAR model for hDPP III inhibition was developed using four Dragon descriptors (Rww, Mats3e, BELe4, and nCs), which can explain 82% of the inhibitory activity. Docking analysis of the semi-closed form of hDPP III in a complex with the most potent compounds indicates the structural features of the benzimidazole derivatives important for the binding at the hDPP III active site.

Synthesis and Characterization of Octahedral Ni(II) and Cu(II) Complexes With Imidazole‐Based Ligands: Structural, DFT, and Molecular Docking, Enhanced Antimicrobial, and Anti‐Inflammatory Activity

ABSTRACTThis study presents the synthesis, characterization, and biological evaluation of novel Ni(II) and Cu(II) metal complexes formed with imidazoleacetic acid (IA) and an imidazole‐based ligand (IM). The novelty of this work lies in the development of these metal–ligand frameworks and their enhanced biological properties, which surpass those of their free ligands. A comprehensive suite of analytical techniques, including elemental analysis, IR spectroscopy, magnetic moment measurements, electronic spectra, mass spectrometry, thermal analysis, and DFT calculations, confirmed the successful formation of the NiIAIM and CuIAIM complexes with a 1:1:1 (M:IA:IM) stoichiometry and octahedral geometry. DFT calculations revealed that metal coordination effectively lowered the energy gap, increasing the complexes softness and reactivity, thereby enhancing their predicted biological activity. Antimicrobial studies demonstrated that both NiIAIM and CuIAIM complexes exhibited superior antibacterial potency against Gram‐positive and Gram‐negative bacteria compared to their free ligands, with activity comparable to the standard antibiotic Chloramphenicol. Furthermore, both complexes showed significant antifungal efficacy against Candida albicans and Aspergillus niger, again outperforming the uncoordinated ligands. Minimum inhibition concentration (MIC) values further validate their potent antimicrobial effects. Additionally, the complexes displayed promising anti‐inflammatory activity, with the CuIAIM complex demonstrating the highest potency, approaching the efficacy of standard drugs based on IC50 values. Molecular docking studies against DNA gyrase B confirmed the CuIAIM complex as the most potent candidate, showing strong binding affinity through multiple hydrogen bonds with key amino acid residues, highlighting its potential antibacterial mechanism. In conclusion, the synthesized NiIAIM and CuIAIM complexes represent promising new antimicrobial and anti‐inflammatory agents, with significantly enhanced biological activity compared to their free ligands. These findings pave the way for further exploration of metal‐based therapeutics in combating infectious diseases and inflammation.

Design, Synthesis, and Molecular Profiling of Pyrimidine-Furan Derivatives Targeting EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S in NSCLC: In Vitro and In Silico Evaluation.

Epidermal growth factor receptor (EGFR) mutations, especially in non-small cell lung cancer (NSCLC), present significant challenges to targeted therapies due to acquired resistance. This study reports the synthesis and evaluation of a series of pyrimidine-furan derivatives as potential anticancer agents. The compounds were screened using MTT and brine shrimp lethality assays, identifyingR2,R10, andR12as the most potent against NSCLC cell lines, particularly NCI-H522 and NCI-H1975. CompoundR12was most potent and selective against NCI-H522, with an IC50value of 0.95 ± .02 µM. EGFR inhibition assays confirmedR12effectiveness with IC50values of 1.62 ± 0.15 µM, 0.49 ± 0.23 µM, and 0.98 ± 0.02 µM against EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S, respectively. The compoundR12led to the cell cycle arrest in the G2/M and S phase of NCI-H522 cells with an increase in apoptosis. Molecular docking and dynamics studies revealed strong binding affinity to EGFR (ΔG = -10.2 kcal/mol, Ki = 32.73 nM), stable protein-ligand interactions. R12 also displayed antioxidant properties (DPPH IC50 = 12.11 ± 8.96 µM, H2O2 IC50 = 8.89 ± 1.72 µM). DFT and ADMET analysis predicted favorable pharmacokinetics, suggesting R12 potential as a promising lead for overcoming EGFR mutations, including triple mutations.

New Antioxidant Triphenol-Derived Hydrazide-Hydrazone Thiazole: Formation and Analysis of Inclusion Complex with β-CD Using Experimental and Computational Approaches

A new water-soluble not-colored antioxidant (Z)-N′-(4-(3,4-dihydroxyphenyl)-3-ethylthiazol-2(3H)-ylidene)-4-hydroxybenzohydrazide hydrochloride (DHTH) was obtained and characterized. The interaction between DHTH and β-CD was studied by experimental thermodynamic methods such as isothermal titration calorimetry (ITC) and 1H NMR spectroscopy and confirmed by in silico calculations. Thermodynamic data indicated that the inclusion process is driven by enthalpy, predominantly as a result of the guest–host hydrophobic interactions. 1H NMR measurements were applied to study the interaction with β-CD by changing the studied compound concentration in the solution. UV-vis titration and in vitro antiradical assay were performed, to study the antioxidant activity of DHTH, free and included in β-CD. A molecular docking study added supplementary insight to the experimental analyses regarding the binding conformation of the new polyphenolic compound to β-CD.

Isolation and Characterization of Phytoconstituents from Lepidium meyenii Roots, Antioxidant Activity and Molecular Docking Analysis for Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. Oxidative stress and cholinergic dysfunction are key contributors to its pathogenesis. Objective: This study aimed to characterize the isolated compounds of Lepidium meyenii roots and assess its neuroprotective and anti-oxidant properties. Methods: Phytochemical screening, compound isolation, and characterization were performed on the ethyl acetate extract. Antioxidant activity was assessed using DPPH, NO, and H2O2 assays. Enzyme inhibition studies for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were conducted in vitro. Molecular docking studies were performed to evaluate binding affinities of isolated compounds to AChE and BChE, and in vitro experiments were carried out to assess cognitive and motor function improvement. Results: The isolated compound quercetin and ergosterol exhibited significant antioxidant activity in DPPH (IC50- 35.65 ± 0.064 and 49.54 ± 0.075 μg/mL), NO (IC50- 30.48 ± 0.092 and 38.73 ± 0.030 μg/mL), and H2O2 (IC50- 24.8 ± 0.17 and 51.4 ± 0.13 μg/mL) assays. In vitro studies demonstrated potent inhibition of AChE and BChE enzymes. Molecular docking confirmed strong binding affinities of the isolated compounds with AChE and BChE. Furthermore, in vitro studies revealed that Lepidium meyenii treatment improved cognitive and motor functions progressively. Conclusion: The findings suggest that Lepidium meyenii possesses neuroprotective properties, likely mediated by its antioxidant activity and enzyme inhibition potential. These results highlight Lepidium meyenii as a promising candidate for the treatment of AD and other neurodegenerative disorders.

Enhancement of bioactivity and molecular docking analysis of bioglass loaded zein and sodium alginate composite beads for biomedical applications

This study intends to conduct both in-vitro and in-silico investigations to assess the bioactivity of newly developed zein/sodium alginate (SA) composite beads. These beads, prepared using the dropwise method, were infused with different concentrations (10%, 20%, 30%, and 40%) of bioglass (BG). These BG-loaded zein/SA- composites were formed into beads with calcium chloride (CaCl2, 5%) as a crosslinking agent. The resulting composite beads were characterized using various techniques (XRD, FTIR, SEM, and EDXA) both before and after in vitro testing in Simulated Body Fluid (SBF). A 3D model of zein was constructed using I-TASSER and validated through PROCHECK and ERRAT servers. The interaction forces between the zein protein and sodium alginate were analyzed in silico using molecular docking with Autodock vina and PyMOL software. The results showed that the formation of a hydroxyapatite (HA) layer on the surface of the BG-loaded zein/SA composite beads confirmed their biological activity, which increased with higher BG content. The results suggest that zein/SA composite beads loaded with bioglass (BG), exhibiting good bioactivity, are suitable for use in bio-tissue engineering applications. A molecular docking study revealed that sodium alginate (SA) can interact with zein through van der Waals forces and hydrogen bonds, leading to the formation of stable complexes. This zein/SA complex is well-suited for carrying bioglass (BG) and has potential applications as a drug carrier in a drug delivery system. Based on the results, our study shows that BG-loaded Zein/SA composite beads are bioactive materials, and can be used in tissue engineering and improve the deposition of new HA, consequently enhancing bone generation. In addition, the prepared composite beads can serve as an excellent drug carrier (future work).

Identification of key active site positions controlling the chemoselectivity of Aspergillus brasiliensis unspecific peroxygenase.

Heme-containing unspecific peroxygenases (UPOs) have catched significant attention as biocatalysts for oxidation reactions due to their ability to function without expensive nicotinamide cofactors. In our recent study, the UPO from Aspergillus brasiliensis (AbrUPO) was found to catalyze the aromatic hydroxylation of substituted benzenes, a feature that distinguishes AbrUPO from other reported wild-type UPOs. To elucidate the underlying factors, we examined the active site and substrate access channel of AbrUPO, which contain fewer phenylalanine residues compared to other UPOs that primarily catalyze benzylic hydroxylation. We constructed twenty two AbrUPO variants with single, double, triple and quadruple amino acid substitutions to mimic the active sites or substrate access channels of other UPOs. A number of mutated variants exhibited altered activity and selectivity, and several positions were identified that influence enzyme chemoselectivity. Among them, substitution of alanine at position 186 with bulkier residues such as phenylalanine or leucine led to a shift in chemoselectivity toward alkyl chain hydroxylation of substituted benzenes. Molecular docking studies indicated that the A186F mutation restricts the flexibility and reorientation of ethylbenzene in the active site of AbrUPO, thereby preventing oxidation at the aromatic ring while promoting benzylic hydroxylation.

Design, Synthesis and Anti-Alzheimer's Activity of Some Hybrid Molecule of Oxymatrine Through TGF-β.

This study aimed to investigate novel therapeutic approaches for Alzheimer's disease (AD) by targeting the Transforming Growth Factor-β (TGF-β) pathway using hybrid compounds derived from oxymatrine and amino acids. AD remains a significant challenge in neurodegenerative disorders, necessitating innovative treatments that can mitigate its devastating effects. The TGF-β pathway has been implicated in AD pathogenesis, making it a promising target for therapeutic intervention. The objective of this study was to synthesize and evaluate the anti-AD activity of hybrid molecules combining oxymatrine with different amino acids. These compounds were designed to enhance blood-brain barrier permeability and selectively modulate TGF-β signaling. Hybrid compounds were synthesized based on molecular docking studies. Characterization of synthesized compounds was performed using thin-layer chromatography (TLC), infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectroscopy. Anti-AD activity was assessed using an AD rat model induced by a high-cholesterol diet, employing behavioral tests (radial arm maze and Hebb's Williams maze) and biochemical assays to measure Aβ and TGF-β levels. All hybrid molecules exhibited significant anti-AD activity, with compound 3B demonstrating the highest efficacy at a dose of 100 mg/kg. Biochemical analyses revealed modulation of Aβ and TGF-β levels, indicating the compounds' potential therapeutic effects against AD. This study unveils a new class of hybrid compounds derived from oxymatrine and amino acids that effectively target the TGF-β pathway, offering promising therapeutic potential for AD. These compounds demonstrate neuroprotective properties, suggesting they may mitigate ADrelated pathology, including tau deposition, synaptic dysfunction, and cognitive decline.

Identification of key therapeutic targets in nicotine-induced intracranial aneurysm through integrated bioinformatics and machine learning approaches

BackgroundIntracranial aneurysm (IA) is a critical cerebrovascular condition, and nicotine exposure is a known risk factor. This study delves into the toxicological mechanisms of nicotine in IA, aiming to identify key biomarkers and therapeutic targets.MethodsGene Set Variation Analysis (GSVA), Weighted Gene Co-Expression Network Analysis (WGCNA), and enrichment analyses were conducted on differentially expressed genes (DEGs) from the GSE122897 dataset. Additionally, nicotine-related targets were identified using CTD, SwissTargetPrediction, and Super-PRED databases. Integrative machine learning approaches, such as Random Forest (RF) and Support Vector Machine (SVM), were employed to pinpoint key toxicity targets. Molecular docking and immune cell infiltration analyses were also performed.ResultsDEGs in IA showed significant alterations in metabolic, secretory, signaling, and homeostatic pathways. Several immune and metabolic response pathways were notably disrupted. WGCNA identified 1127 DEGs with 37 overlapping toxic targets between IA and nicotine. ssGSEA revealed substantial upregulation in immune response and inflammation-related processes. Integrative analyses highlighted TGFB1, MCL1, and CDKN1A as core toxicity targets, confirmed via molecular docking studies. Immune cell infiltration analysis indicated significant correlations between these core targets and various immune cell populations.ConclusionThis study uncovers significant disruptions in metabolic and immune pathways in IA under nicotine influence, identifying TGFB1, MCL1, and CDKN1A as critical biomarkers. These findings offer a deeper understanding of IA’s molecular mechanisms and potential therapeutic targets for nicotine-related toxicity.

Biscoumarin Derivatives Bridged Quinazolinedion: Synthesis, Molecular Docking Study, and Cytotoxic Activities

Biscoumarin Derivatives Bridged Quinazolinedion: Synthesis, Molecular Docking Study, and Cytotoxic Activities

Uncovering the anti-cancer mechanism of cucurbitacin D against colorectal cancer through network pharmacology and molecular docking

Colorectal cancer is a significant global health challenge due to chemoresistance, necessitating new treatments. Cucurbitacin D, with its anti-cancer properties, shows promise, but its effects on colorectal cancer are not well understood. We investigated the impact of cucurbitacin D on colorectal cancer cell lines using MTT assays and Annexin V/7-AAD staining followed by flow cytometry for apoptosis analysis. Public databases helped identify cucurbitacin D and colorectal cancer-related gene targets for network pharmacology analysis. Protein–protein interaction networks were constructed using STRING and analyzed in Cytoscape. Gene ontology and KEGG pathway enrichment analyses were performed using ClueGo. Molecular docking studies were conducted via Autodock Vina and visualized in Discovery Studio. Western blot assessed protein expression changes in key targets under cucurbitacin D. Cucurbitacin D dose-dependently reduced colorectal cancer cell viability and induced apoptosis. Network pharmacology pinpointed crucial targets like STAT3, AKT1, CCND1, and CASP3. Molecular docking confirmed strong interactions with these targets. Enrichment analysis highlighted involvement in the 'PI3K-AKT,' 'JAK-STAT,' and 'ErbB' signaling pathways. These findings suggest cucurbitacin D as a potential anti-colorectal cancer agent, demonstrating significant effects on cell viability and apoptosis, and engaging critical cancer-related pathways, making it a promising candidate for further colorectal cancer therapeutic research.

Bioactivity of novel isoxazole-fused heterocycles: comprehensive antimicrobial, antioxidant activities, SwissADME predictions, molecular docking, and DFT analysis.

Among the foremost goals for organic chemists is to discover novel approaches for the synthesis of a particular heterocyclic and its design. Our approach focused on the vital precursor 4-acetyl-3-phenylisoxazol-5(4H)-one 3, as this molecule has an endocyclic carbonyl function in position 5 adjacent to the substituted acetyl function at site 4. Therefore, compound 3 was a crucial component of many types of fused isoxazole. The investigators provide a straightforward synthesis of fused isoxazole from the following categories: pyrano[3,2-d]isoxazole 4 & 6, isochromeno[4,3-d]isoxazole 5, isoxazolo[4',5':5,6]pyrano[3,4-c]pyridine 7, thieno[3',4':4,5]pyrano [3,2-d]isoxazole 8, pyrazolo[4,3-d]isoxazole 10a,b and 11a,b, and isoxazolo[4,5-c]pyridazine derivatives 14a,b. The target compounds and their structures were supported by the results of 1H-NMR, IR and mass spectroscopy. Molecular docking studies highlighted strong binding affinities to bacterial enzymes crucial for cell wall synthesis, while DFT calculations provided deep insights into their electronic properties and stability. Additionally, the antioxidant potential of compounds 11a,b was assessed using DPPH and ABTS assays, showing impressive concentration-dependent activity. Addressing the critical issue of antibiotic resistance, especially due to β-lactamases, molecular docking affirmed the high binding propensity of these derivatives with essential β-lactamase proteins (PDB: 1CK3, 6MU9, and 6W2Z). These findings underscore the promise of isoxazoline derivatives as powerful antimicrobial and antioxidant agents, paving the way for further development in combating bacterial resistance and oxidative stress.

Preliminary assessment of cardiovascular effects and chemoinformatic analysis of total aqueous extract and fractions from Inula viscosa leaves.

Inula viscosa (L.) Aiton [Dittrichia viscosa (L.) Greuter] (Asteraceae) is an evergreen perennial herb that grows in different regions of the Mediterranean Basin. It has been particularly used for the treatment of hypertension and diabetes in the Eastern and South-East regions of Morocco. To assess the cardiovascular effects of total aqueous extract and various fractions of Inula viscosa leaves in rat-isolated hearts and aortic rings, and to investigate the potential mechanisms of action of the most active extract(s). In Langendorff's isolated heart system, heart rate (HR) and left ventricular developed pressure (LVDP) were measured for three increasing concentrations of TAE, DCMF, EAF, BF, and AF (0.003, 0.03, and 0.3 mg/mL). Propranolol (1.5 × 10⁻5M) and Verapamil (2 × 10⁻7M) were used to investigate the potential mechanisms of action of both EAF and BF. In isolated intact aortic rings, four cumulative concentrations of EAF and BF (0.0001, 0.001, 0.01, and 1mg/mL) were tested for their vasorelaxant effects. The role of the endothelium in the vasorelaxant effect of EAF was examined by denuding aortic rings. To explore the involvement of the nitric oxide (NO) pathway, β-adrenergic receptors, calcium channels, and the sarco/endoplasmic reticulum Ca2⁺-ATPase (SERCA) pump, intact aortic rings were preincubated with L-NAME (10⁻4M), Propranolol hydrochloride (10⁻6M), Verapamil hydrochloride (10⁻5M), and Thapsigargin (10⁻7M), respectively. The hypotensive effects of both BF (125mg/kg) and EAF (125mg/kg) were evaluated indirectly using the tail-cuff method in normotensive rats. Additionally, the antioxidant activity, as well as the total phenolic and flavonoid contents of all prepared extracts, were determined. To further investigate the antioxidant properties, computational analysis was conducted to determine the bond dissociation energies of the hydroxyl groups on the B-ring of luteolin and quercetin, which are present in EAF and BF, respectively. Finally, an UHPLC analysis was performed for BF. In isolated perfused hearts, TAE induced a dose-dependent positive inotropic effect, accompanied by mild bradycardia. EAF exhibited both positive inotropic and chronotropic effects in a concentration-dependent manner. BF demonstrated a highly dose-dependent, selective positive inotropic effect (LVDP = 76.5 ± 19.2% vs. control at 0.3mg/mL) with no significant impact on HR. Our findings suggest that BF acts independently of β-adrenoreceptor-dependent pathways, whereas EAF may exert its effects through β-agonistic activity. Additionally, Ca2⁺ channels may play a role in the effects of both fractions. In phenylephrine-precontracted thoracic arteries, both BF and EAF induced concentration-dependent vasorelaxation, with EAF producing the most potent vasorelaxant effect (Emax = 84.16 ± 3.68%). EAF mediates an endothelium-independent vasodilatory response through inhibition of voltage-dependent Ca2⁺ channels and activation of the SERCA pump. BF also demonstrated a significant hypotensive effect in vivo. Among the various extracts, BF contained the highest total phenolic and flavonoid contents and exhibited the strongest DPPH scavenging activity (IC50 = 7.13µg/mL). Molecular docking studies supported these findings, indicating that quercetin is more effective at scavenging free radicals than luteolin. Phytochemical study of BF revealed the presence of phenolic compounds such as chlorogenic acid, three isochlorogenic acids (A, B and C), tri-caffeoylhexaric acid, methyl 3,5-dicaffeoylquinic acid, quercetin-3-glucuronide and the new molecule 1,3,4,5-tetracaffeoylaltraric acid. This study revealed a novel and potent selective inotropic effect of the BF fraction from I. viscosa leaves, characterized by the absence of tachycardia and independence from β-adrenergic receptors in isolated rat hearts.

Binding Affinity of Synthetic Cannabinoids to Human Serum Albumin: Site Characterization and Interaction Insights

Background/Objectives: High-performance affinity chromatography (HPAC) was used to investigate the binding affinity of a series of synthetic cannabinoids, a widely abused class of new psychoactive substances, to human serum albumin (HSA) and obtain insights into the binding sites. To better understand the recognition mechanisms, molecular docking studies were conducted. Methods: Binding affinity was assessed through zonal elution approach Additionally, displacement chromatography with site-specific probes provided insights into the HSA binding sites of five synthetic cannabinoids. Results: That these drugs exhibit extensive binding to HSA, with values ranging from 98.7% to 99.9%. Competition for site I was observed between warfarin and four synthetic cannabinoids (5F-AMB, AB-PINACA, AMB-FUBINACA, and AB-CHMINACA). Furthermore, AB-CHMINACA also competed with L-tryptophan for site II. The binding affinity of all synthetic cannabinoids increased in the presence of (S)-ibuprofen. Molecular docking studies supported the experimental findings, reinforcing the insights gained. Conclusions: The key novelty of this study lies in analyzing, for the first time, the binding affinity of synthetic cannabinoids to HSA through HPAC and molecular docking. These results may improve our understanding of their toxicokinetic behavior and help in predicting possible competitive interactions that could influence HSA binding and, consequently, their activity and toxicity. This study is the first to describe the binding affinity of synthetic cannabinoids to HSA, elucidate their recognition mechanisms, identify binding sites, and characterize their interactions with the protein.