Molecular Docking Studies Research Articles

Position Matters: Effect of Nitro Group in Chalcones on Biological Activities and Correlation via Molecular Docking

A series of nine nitro group-containing chalcones were synthesized to investigate their anti-inflammatory and vasorelaxant activities via in vivo, ex vivo, and in silico studies. The anti-inflammatory effects of the compounds were evaluated via a TPA-induced mouse ear edema model, and the vasorelaxant effects were evaluated via an isolated organ model in addition to molecular docking studies. The compounds with the highest anti-inflammatory activity were 2 (71.17 ± 1.66%), 5 (80.77 ± 2.82%), and 9 (61.08 ± 2.06%), where the nitro group is located at the ortho position in both rings, as confirmed by molecular docking with COX-1 and COX-2. The compounds with the highest vasorelaxant activity were 1 (81.16 ± 7.55%), lacking a nitro group, and 7 (81.94 ± 2.50%), where the nitro group is in the para position of the B ring; both of these compounds interact with the eNOS enzyme during molecular docking. These results indicate that the position of the nitro group in the chalcone plays an important role in these anti-inflammatory and vasorelaxant activities.

Synthesis of New Imidazolo‐Benzenesulfonamide Linked 1,2,3‐Triazoles as Potent Antibacterial and Antibiofilm Agents

AbstractIn search of better antibacterial and antibiofilm agents, this report presents a series of novel 1,2,3‐triazole‐imidazole‐benzenesulfonamide derivatives that were synthesized and evaluated for their antibacterial and antibiofilm activity in vitro. Antibacterial activity against three Gram‐positive bacterial strains, B. subtilis, S. aureus, and S. epidermidis, was evaluated. Among all the tested compounds, 4‐methyl‐N‐(1‐methyl‐1H‐imidazol‐2‐yl)‐N‐((1‐(4‐(trifluoromethyl)phenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)benzenesulfonamide and N‐((1‐(3,5‐difluorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐4‐methyl‐N‐(1‐methyl‐1H‐imidazol‐2‐yl)benzenesulfonamide exhibited potent antibacterial activity against S. aureus and B. subtilis bacterial strains. Biofilm profiles for the potent compounds and it was observed from the results that the above two active compounds displayed promising biofilm inhibition against B. subtilis and S. aureus, with MIC values ranging between 2.19 ± 0.37 and 3.38 ± 0.35 µg/mL. Furthermore, potent compounds screened for their in silico molecular docking studies against penicillin‐binding protein and compound N‐((1‐(3,5‐dichlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐4‐methyl‐N‐(1‐methyl‐1H‐imidazol‐2‐yl)benzenesulfonamide show highest binding energy as compared to the standard and remaining compounds.

Promising Novel Heterocyclic Drug Candidates: Synthesis, Characterization, DFT Calculations and In Silico Investigations of Anticancer Behaviors

In recent years, the inadequacy and high costs of current cancer treatment drugs have led to an increase in research focused on the design and synthesis of new compounds with potential applications in this field and the evaluation of their anticancer properties using in silico methods. For this purpose, four novel heterocyclic compounds (6–9) were synthesized and characterized using spectroscopic techniques. The DFT approach and B3LYP/6-311G(d,p) basis set were used to compare theoretical data with experimental ones and to obtain optimized geometries. It was observed that experimental and theoretical data were in harmony. In silico techniques were used to investigate the potential of synthesized compounds as drug candidates. ADMEt results have shown that all synthesized compounds have Lipinski’s rule of five which has searched criteria in drug candidates. Molecular docking studies were also performed against cancer-related proteins. The highest docking score between 2XIR protein and compound 8 was found to be −11.7 kcal/mol, while the lowest was −8.2 kcal/mol between 1MP8 protein and compound 9. To do meaningful comparisons standard drugs were also used in Molecular Docking studies. It was observed that all synthesized molecules had higher docking scores than standard drugs except ifebemtinib. It can be suggested that based on ADMET and molecular docking studies compound 8 has the potential to be a drug candidate after further investigations such as in vitro, in silico, etc., have been performed in this area.

Design, synthesis, in vitro, and in silico study of benzothiazole-based compounds as a potent anti-Alzheimer agent.

Alzheimer's disease (AD) is a multifactorial neurological disorder that involves multiple enzymes in the process of developing. Conventional monotherapies provide relief, necessitating alternative multi-targeting approaches to address AD complexity. Therefore, we synthesize N-(benzo[d]thiazol-2-yl) benzamide-based compounds and tested against monoamine oxidases (MAO-A and MAO-B). In the in vitro experimental evaluation of MAO, all the compounds displayed remarkable potency, having IC50 values in the lower micromolar range. The most potent MAO-A inhibitor was (3e) with an IC50 value of 0.92 ± 0.09μM, whereas, (3d) was the most potent inhibitor of MAO-B with an IC50 value of 0.48 ± 0.04μM. Moreover, Enzyme kinetics studies revealed that the potent inhibitors of MAO-A and MAO-B showed competitive mode of inhibition. Furthermore, molecular docking studies were also performed to confirm the mode of inhibition and obtain an intuitive picture of potent inhibitors. It also revealed several important interactions, particularly hydrogen bonding interaction. All the newly synthesized compounds showed good ADME pharmacokinetic profile and followed Lipinski rule; these compounds represent promising hits for the development of promising lead compounds for AD treatment.

New acid anhydride from Phalaris canariensis with antimicrobial activity assessed through in vitro and in silico approaches

In this study, a novel fatty acid anhydride, named phalarisin 1, was successfully isolated from the ethyl acetate extract of Phalaris canariensis growing in Tunisia. The structural characterisation of the compound was achieved through various spectroscopic techniques including FT-IR, 1D and 2D-NMR spectroscopy, as well as acidic hydrolysis analyses. Remarkably, phalarisin exhibited potent antimicrobial properties against a range of pathogens including Micrococcus luteus, Bacillus subtilis, Fusarium oxysporum, and Fusarium phylophylum, with minimum inhibitory concentrations (MICs) ranging from 31.25 to 62.5 μg/mL. To grasp the antimicrobial potential of compound 1, molecular docking studies were performed and they furnished evidence indicating its ability to bind to proteins in bacteria and fungi that are pivotal for drug resistance.

Validated HPTLC Method for Detection of Kaempferol in <i>Moringa oleifera</i> Leaf Extract and Investigation of its Antidiabetic Potential by <i>In Vitro</i> and <i>In Silico</i> Studies

Background: Exploring traditional treatments offers valuable foundations for the innovation of new pharmaceuticals for the management of diabetes mellitus and its complications. Validation of plant extract by suitable chromatographic techniques is a part of standardization procedures. Moringa oleifera is one such traditionally used plant to be explored. Aim: The study explores the antidiabetic potential of M. oleifera through both in vitro and in silico explorations along with HPTLC method development and validation for estimation of kaempferol in M. oleifera extract. Method: Plant extract was prepared by maceration method using ethanol: water (70:25) and followed by Soxhlet(95% ethanol). Pharmacognostical analysis was conducted. In silico and in vitro antidiabetic and antioxidant studies were conducted, as well as quality control analysis was done using HPTLC method the mobile phase used was toluene: ethyl acetate: formic acid: methanol: (6:3:0.3:1v/v/v/v). Results: HPTLC analysis showed the presence of kaempferol, and the method was validated as per ICH guidelines. According to reports on molecular docking studies, several phytocompounds inhibited when porcine pancreatic α-amylase (PPA) complexed with a carbohydrate inhibitor (PDB ID: 4W93).The hydroalcoholic extract was discovered to have the ability to inhibit α-amylase, with IC50 values of 57.38588±1.92 μg/mL and 32.51564±1.59 μg/mL for standard acarbose, respectively. Conclusion: Overall, this research provides comprehensive data for the estimation of kaempferol in Moringa oleifera by HPTLC and presents valuable evidence on its antidiabetic potential both in vitro and in silico.

Synthesis of para‐Carboxamidostilbene Derivatives as Antihyperglycemia Agents and Their In Silico ADMET and Molecular Docking Studies

AbstractIn this project, para‐carboxamidostilbene derivatives were synthesized using the Heck coupling reaction, confirmed through various analytical techniques such as FT‐IR, HRMS, and NMR analyses, and tested in vitro to evaluate their α‐amylase inhibitory activity. In silico molecular docking was employed to model the binding interactions of compounds with α‐amylase. Pharmacokinetic properties (ADME) and drug‐likeness were also examined. Structure activity relationship (SAR) analysis was conducted to establish the relationship between the chemical structure and α‐amylase inhibitory activity. The synthesized compounds exhibited significant α‐amylase inhibitory activity with IC50 values ranging from 15.0 to 37.5 µM in comparison with acarbose (IC50 = 30.2 ± 1.9 µM). Among them, compounds 6d–6f and 7c–7f demonstrated promising inhibitory activity. Furthermore, molecular docking studies revealed strong interactions between the studied molecules and the α‐amylase binding pocket. The drug‐likeness prediction results indicated that all synthesized compounds adhered to Lipinski's rule of five, suggesting their suitability as drug‐like molecules. Additionally, the assessment of ADMET properties indicated favorable absorption profiles, particularly in terms of human intestinal absorption (HIA). Overall, this study successfully identified several para‐carboxamidostilbene derivatives as potential α‐amylase inhibitors for the treatment of T2DM.

Organotin(IV) complexes of tridentate (ONO) hydrazone ligands: synthesis, spectral characterization, antituberculosis, antimicrobial, anti-inflammatory, molecular docking and cytotoxicity studies.

Infectious diseases have a significant impact in the historical trajectory of humanity, exerting profound influence on societies, driving advancements in medical science, and significantly impacting individuals on a worldwide scale. Consequently, this research endeavours to identify potent agents combatting tuberculosis, inflammation, and microbial deformities. The investigation focuses on hydrazones (1,2) endowed eight organotin(IV) complexes, where hydrazones were derived from 2-acetyl-1H-indene-1,3(2H)-dione and 2-phenoxypropanehydrazide/2-(2,4-dichlorophenoxy)propanehydrazide. All compounds underwent thorough characterization utilizing a variety of spectral and analytical techniques including, multinuclear NMR, FT-IR, HRMS, UV-Vis, SEM-EDAX, TGA, XRD, molar conductance measurements, establishing the pentacoordinated environment around tin(IV) ion with tridentate (ONO) mode of chelation of hydrazones. Powder XRD revealed the ligand's crystalline and complexes' semi-crystalline nature, while thermal analysis indicated two-step decomposition leaving tin oxide residue. In vitro evaluations utilize microplate alamar blue assay for assessing anti-tuberculosis activity, serial dilution technique for antimicrobial efficacy, and bovine serum albumin method for evaluating anti-inflammatory properties. The complexes exhibited higher biological activities than their respective ligands and the activity of the complexes follow the order: Ph2SnL1-2 > Bu2SnL1-2 > Et2SnL1-2 > Me2SnL1-2. Among them, phenyl complex (10) [Ph2SnL2] displays superior efficacy against TB dysfunction (MIC: 0.0180 ± 0.009μmol/mL) and also demonstrates exceptional potency in combating inflammation (IC50: 7.27 ± 0.04μM), and microbial (MIC: 0.0045μmol/mL) infections, comparable to standard drugs. Additionally, cytotoxicity testing against vero cell line revealed decreased toxicity at lower concentrations, and attenuated by chelation. Phenyl complex (10) [Ph2SnL2] shows promising cytotoxicity at 3.12µg/mL (19.29 ± 0.09%). Further, The diphenyltin(IV) complex (10), identified as the most effective against TB, shows stronger binding to key 3PTY protein residues (-42.2kJ/mol) compared to ligand (2) (-33.4kJ/mol), correlating with its superior anti-tuberculosis potency in biological assays. This comprehensive approach aims to actively contribute to ongoing initiatives addressing infectious diseases, thereby advancing global health and overall well-being.

Elucidation of the Binding Interaction between β-sitosterol and Lysozyme using Molecular Docking, Molecular Dynamics and Surface Plasmon Resonance Analysis.

In this study, the binding behavior of β-sitosterol with lysozyme (LZM) was elucidated by surface plasmon resonance (SPR), computational molecular docking and molecular dynamics simulation studies. Chicken egg white lysozyme (CEWLZM) served as a model protein. Tri-N-acetylchitotriose (NAG3) was used in the redocking experiments to generate precise binding location of the protein. β-sitosterol displayed a slightly better binding energy (-6.68±0.04 kcal/mol) compared to NAG3. Further molecular dynamics simulations and MMPBSA analysis revealed that residues Glu35, Gln57-Asn59, Trp62, Ile98, Ala107 and Trp108 contribute to the binding energy. Then, 2.5 mg/mL CEWLZM, 1X PBS buffer (pH 7.4) as running and coupling buffers, 30 µL/min as flow rate were applied for SPR analysis. Serial β-sitosterol injections (20-150 μM) were performed through SPR sensor surface. According to SPR binding study, KD value for β-sitosterol-CEWLZM binding interaction was calculated as 71.34±9.79 µM. The results could provide essential knowledge for nutrition, pharmaceutical science, and oral biology.

Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor

Abstract Nowadays, the physiopathological and molecular mechanisms of multiple diseases have been identified, thus helping scientists to provide a clear answer, especially to those ambiguities related to chronic illnesses. This has been accomplished in part through the contribution of a key discipline known as bioinformatics. In this study, the bioinformatics approach was applied on four compounds identified in Centaurea tougourensis, using two axes of research: an in silico study to predict the molecular characteristics, medicinal chemistry attributes as well as the possible cardiotoxicity and adverse liability profile of these compounds. In this context, four compounds were selected and named, respectively, 2,5-monoformal-l-rhamnitol (compound 1), cholest-7-en-3.beta.,5.alpha.-diol-6.alpha.-benzoate (compound 2), 7,8-epoxylanostan-11-ol, 3-acetoxy- (compound 3), and 1H-pyrrole-2,5-dione, 3-ethyl-4-methyl- (compound 4). The second part looked into molecular docking, which objective was to evaluate the possible binding affinity between these compounds and the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor. Results indicated that compounds 1 and 4 were respecting Pfizer and giant Glaxo-SmithKline rules, while compounds 2 and 3 exhibited an optimal medicinal chemistry evolution 18 score. The structural and molecular features of almost all tested compounds could be considered optimal, indicating that these phyto-compounds may possess drug-likeness capacity. However, only compounds 1 and 4 could be considered non-cardiotoxic, but with a level of confidence more pronounced for compound 1 (80%). In addition, these four biocompounds could preferentially interact with G protein-coupled receptor, ion channel, transporters, and nuclear receptors. However, the heat map was less pronounced for compound 2. Data also indicated that these four compounds could possibly interact with serotonin 5-HT2A receptor, but in an antagonistic way. This research proved once again that plants could be crucial precursors of pharmaceutical substances, which could be helpful to enrich the international pharmacopoeia.

Molecular Docking Studies of Synthesized Pyridazinone Scaffolds as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Pyridazinone derivatives, 6-aryl-pyridazinone (2a–f) and 2-(N-substituted)-6-aryl-pyridazinone (3a–h) derivatives were synthesized and assessed for cytotoxicity action using brine shrimp assessment method and in silico molecular studies. In silico molecular study of pyridazine derivatives used as NNRTIs and Doravirine is used as reference drug. The compounds were investigated for docking modes onto probable binding sites with HIV reverse transcriptase. The majority of these demonstrated favorable binding interactive connections with the active receptor domain. The majority of the compounds exhibited a remarkable docked binding affinity score when compared with the reference drugs. Among the synthesized pyridazine derivatives, compounds 3a and 3c–h exhibited a good docking score. For the designed compounds, in silico ADME assessment indicated the favorable physicochemical properties to be a suitable drug candidate. The synthesized compounds could serve as a novel alternative in designing safe and effective anti-HIV options with reverse transcriptase inhibitor potential. In the cytotoxicity study, all the compounds were evaluated at dose levels 10, and 20 (μg/mL), and potassium dichromate was used as a reference. Compounds 2c and 2e have shown potent lethality through LC50 2.23 and 3.20 μg respectively. Various compounds, including 2a, 2b, 2d, and 2f have demonstrated significant cytotoxicity. Their LC50 values are 7.58, 6.76, 8.91, and 4.46 μg, respectively. Additionally, compounds 3b and 3d exhibited potent lethality with LC50 values of 4.023 and 4.20 μg. Other compounds, namely 3g, 3f, 3c, 3h, 3a, and 3e, displayed noteworthy cytotoxicity ability13.91, 12.58, 11.91, 11.76, 10.58, 9.76, and 7.46 μg, respectively having LC50 values. This study supports the use of in silico molecular design and the brine shrimp bioassay as a suitable, reliable, and simple method for assessing the bioactivity of compounds. It provides further evidence for their use in medicine.

A biophysical insight into the mechanism of anticancer activity of salicylidene cyclohexanediamine based cobalt and nickel complexes through CT-DNA, BSA binding and docking study

Two novel metal Schiff base complexes, [Co(L)(OH2)(Cl)].2DMF (1) and [Ni(L)].H2O (2) [H2L=N,N'-bis(5-bromo-3-(methoxy)salicylidene)cyclohexane-1,2-diamine] were prepared and structurally characterized through single crystal X-ray crystallography and usual spectroscopic techniques. The inhibitory action of H2L, 1 and 2 via MTT assay on MDA-MB 231, HCT-116, and A549 cell lines was assessed. The complexes exhibit lower IC50 values than the ligand (H2L> 2> 1). On the other hand, with normal human PBMC, they were found to be significantly nontoxic. The interaction of 1 and 2, with CT-DNA and serum albumin (BSA) through different biophysical experiments was checked to have a plausible understanding of their anticancer activity as well as pharmacological relevance. These investigations inferred that 1 had a greater affinity for CT-DNA and BSA than 2. 1 interacts with CT-DNA through intercalation whereas 2 exhibits a mixed mode of interaction (intercalation and groove binding). The complexes exhibit a predominantly hydrophobic interaction with BSA, which is static in nature and causes a prominent structural change of BSA, from α-helix to β-sheet. The rate of hydrolysis of the phospho-ester bond in PNPP was found to be four times faster with 1 than with 2. A molecular docking study was conducted to gain a deeper insight into the molecular interactions along with possible theoretical binding energies of the complexes with CT-DNA and BSA, and this was found to be in agreement with the experimental findings.

Network Pharmacology Revealing the Therapeutic Potential of Bioactive Components of Triphala and Their Molecular Mechanisms against Obesity.

Obesity, characterized by the excessive accumulation of fat, is a prevalent metabolic disorder that poses a significant global health concern. Triphala, an herbal combination consisting of Phyllanthus emblica Linn, Terminalia chebula Retz, and Terminalia bellerica (Gaertn) Roxb, has emerged as a potential solution for addressing concerns related to obesity. This study aimed to investigate the network pharmacology and molecular docking of Triphala to identify its bioactive ingredients and their interactions with pathways associated with obesity. The bioactive compounds present in Triphala and genes linked to obesity were identified, followed by an analysis of the protein-protein interaction networks. Enrichment analysis, including Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis, was conducted. Prominent genes and compounds were selected for further investigation through molecular docking studies. The study revealed a close correlation between obesity and the AKT1 and PPARG genes. The observed binding energy between beta-sitosterol, 7-dehydrosigmasterol, peraksine, α-amyrin, luteolin, quercetin, kaempferol, ellagic acid, and phyllanthin with AKT1 and PPARG indicated a favorable binding affinity. In conclusion, nine compounds showed promise in regulating these genes for obesity prevention and management. Further research is required to validate their specific effects.

Distinct Adjacent Substrate Binding Pocket Regulates the Activity of a Decameric Feruloyl Esterase from Bacteroides thetaiotaomicron.

Understanding how the human gut microbiota contribute to the metabolism of dietary carbohydrates is of great interest, particularly those with ferulic acid (FA) decorations that have manifold health benefits. Here, we report the crystal structure of a decameric feruloyl esterase (BtFae) from Bacteroides thetaiotaomicron in complex with methyl ferulate (MFA), revealing that MFA is situated in a noncatalytic substrate binding pocket adjacent to the catalytic pocket. Molecular docking and mutagenesis studies further demonstrated that the adjacent pocket affects substrate binding in the active site and negatively regulates the BtFae activity on both synthetic and natural xylan substrates. Additionally, quantum mechanics (QM) calculations were employed to investigate the catalytic process of BtFae from substrate binding to product release, and identified TS_2 in the acylation step is rate-limiting. Collectively, this study unmasks a novel regulatory mechanism of FAE activity, which may contribute to further investigation of FA-conjugated polysaccharides metabolism in the human gut.

GC-MS Profiling, Pharmacological Predictions, Molecular Docking, and ADME Studies of Different Parts of Thymus Linearis against Multiple Target Proteins in Wound Healing.

Thymus linearis from the Himalayan woodlands of Gilgit Baltistan, Pakistan, is a phytomedicine that has not been well-studied. Traditionally, it is recognized for its potential in treating conditions such as dermatitis, psoriasis, weight loss, and discomfort. The study investigates the wound-healing properties of methanolic extracts from the plant's stems, leaves, and roots. GC-MS disclosed cadaverine, dihydroxy-3,3-dimethyl-3-hydroxy-N-isopropylbutyramide, phthalic acid-di(2-propylpentyl)ester, and benzo[h]quinolone-2,4-dimethyl in stem along with betamethasone velerate, 17-pentatriacontene, 1,1-cyclobutanedicarboxmide, heptadecane-9-hexyl, cyclohexanol-2-methylene-3(1-methylethenyl) and pentacyclo[12.3.0.0(1,13).0(2,10).0(5,9)]hepatodecane-6-ol-15-one in leaf extracts and 2-myristynonyl pantetheine, 7,8-epoxylanostan-11-ol-3-acetoxy, heneicosane (1-(1-ethyl propyl)), 2-piperidinone-N-[4-bromobutyl] and 1-monolinoleoylglycerol trimethyl silyl ether in the root extract. The antioxidant activity was assessed using several assays including DPPH, bound iron %, ABTS, total flavonoid content, and total phenolic content. The methanolic stem extract (MSE) showed the highest antioxidant capacity compared to the leaf and root extracts. The stem extract demonstrated the highest wound-healing potential, followed by leaves and roots in albino mice. The findings were supported by computational analysis, which revealed that the binding interactions of phytochemicals from stem have more affinity than leaf and root with specific receptor sites. The in-silico analysis ascertains that dihydroxy-3,3-dimethyl-3-hydroxy-N-isopropylbutyramide from MSE is the most effective wound-healing agent. Moreover, ADME predictions demonstrated the drug-like properties of the hit compounds.

Synthesis, modeling, bioactivity, docking, binding energy analysis of new effective piperazine derivatives as effective drug candidates for treatment of Parkinson’s disease

In this study, density functional theory (DFT) calculations were initially conducted to explore the molecular structure, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), LUMO-HOMO energies, as well as the excited states of new piperazine derivatives using the CAM-B3LYP/Def2TZV level of theory. Detailed quantum molecular descriptors for the compounds, including ionization potential (IP), electron affinities (EA), hardness (η), softness (S), electronegativity (μ), electrophilic index (ω), electron-donating power (ω−), electron accepting power (ω+), and energy gap (Eg), were calculated. The chemical properties and bioactivity of these compounds, such as molecular weight, lipophilicity, number of hydrogen bond (HB) donors and acceptors, molar refractivity, polarity, solubility, flexibility and saturation, were also investigated. Subsequently, a molecular docking study was performed to identify effective compounds that could act as strong inhibitors against Parkinson’s Disease. The Michaelis-Menten constant (Km) was determined using the CAM-B3LYP/Def2TZV level of theory. The binding energy between the protein with ID:5CGJ and the organic compounds demonstrated excellent binding affinity. Therefore, the structures: 4-(4-methylpiperazin-1-yl)-4-oxo-N-(4-sulfamoylphenyl)butanamide (21), N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-(morpholinomethyl) benzamide (22), cаn bе usеd for potential application аgаinst Parkinson’s Disease.

Synthesis of Carborane–Thiazole Conjugates as Tyrosinase and 11β-Hydroxysteroid Dehydrogenase Inhibitors: Antiproliferative Activity and Molecular Docking Studies

The presented study depicts the synthesis of 11 carborane–thiazole conjugates with anticancer activity, as well as an evaluation of their biological activity as inhibitors of two enzymes: tyrosinase and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The overexpression of tyrosinase results in the intracellular accumulation of melanin and can be observed in melanoma. The overexpression of 11β-HSD1 results in an elevation of glucocorticoid levels and has been associated with the aggravation of metabolic disorders such as type II diabetes mellitus and obesity. Recently, as the comorbidity of melanomas and metabolic disorders is being recognized as an important issue, the search for new therapeutic options has intensified. This study demonstrates that carborane–thiazole derivatives inhibit both enzymes, exerting beneficial effects. The antiproliferative action of all newly synthesized compounds was evaluated using three cancer cell lines, namely A172 (human brain glioblastoma), B16F10 (murine melanoma) and MDA-MB-231 (human breast adenocarcinoma), as well as a healthy control cell line of HUVEC (human umbilical vein endothelial cells). The results show that 9 out of 11 newly synthesized compounds demonstrated similar antiproliferative action against the B16F10 cell line to the reference drug, and three of these compounds surpassed it. To the best of our knowledge, this study is the first to demonstrate dual inhibitory action of carborane–thiazole derivatives against both tyrosinase and 11β-HSD1. Therefore, it represents the first step towards the simultaneous treatment of melanoma and comorbid diseases such as type II diabetes mellitus.

Piperine exerts anti-inflammatory effects and antagonises the properties of celecoxib and ketoprofen: in vivo and molecular docking studies

This study evaluates the anti-inflammatory effects of a natural product, piperine (PPN), using in vivo and in silico methodologies. In the in vivo segment, inflammation was induced in the right hind paw of young chicks via a formalin (50 μL) injection. PPN was orally administered at doses of 25 and 50 mg/kg with or without celecoxib (CXB) and/or ketoprofen (KPN) (42 mg/kg). The vehicle acted as the negative control group (NC). The in silico analysis predicted the drug-likeness, pharmacokinetics, and toxicity profile of PPN, along with evaluating its binding affinity and ligand-receptor interactions. Results indicate that PPN significantly (p < 0.05) reduced licking frequency and paw edoema in a dose-dependent manner. However, in combination therapy, PPN diminished the effects of both CXB and KPN. PPN showed high affinity (–8.6 kcal/mol) towards the COX-2 enzyme. Therefore, PPN exerts anti-inflammatory effects in chicks through COX-2 inhibition pathways and antagonises CXB and KPN activities.

Bufalin induces ferroptosis by modulating the 2,4-dienoyl-CoA reductase (DECR1)-SLC7A11 axis in breast cancer

Breast cancer (BC) is a leading cause of cancer-related mortality worldwide. 2,4-dienoyl-CoA reductase (DECR1), an auxiliary component of beta-oxidation, has been recognized for its role in enhancing lipid peroxidation and inducing ferroptosis in prostate cancer. However, its involvement in breast cancer remains largely unexplored. Our study revealed a notably elevated expression of DECR1 in breast cancer tissues, which correlated with increased malignant characteristics. Importantly, the overexpression of DECR1 significantly enhanced proliferation and migration capabilities in MDA-MB-231 cells. Through a comprehensive high-content screening approach, we identified bufalin and its derivative as potent inhibitors of DECR1 expression. Notably, bufalin demonstrated the highest binding energy during molecular docking studies and was found to promote the degradation of DECR1 via autophagy and ubiquitination. Furthermore, bufalin induced ferroptosis in MDA-MB-231 cells by modulating levels of malondialdehyde (MDA), triglycerides (TG), reactive oxygen species (ROS) and Fe2+ while downregulating the expression of hormone-sensitive lipase (HSL), ferritin heavy chain protein 1 (FPN), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). These effects were counteracted by DECR1 overexpression. In vivo experiments demonstrated that bufalin inhibited the tumor growth, while decreasing the expression levels of HSL, FPN, SLC7A11, and GPX4, alongside increasing levels of 4-hydroxynonenal (4-HNE). Crucially, the ferroptosis effects induced by bufalin in vivo were also reversed by DECR1 overexpression. Subsequently, we discovered that SLC7A11 interacts with DECR1, inhibition of SLC7A11 led to decreased expression levels of DECR1 along with an accumulation of MDA and Fe2+, effects that were similarly reversed by DECR1 overexpression. Collectively, our findings suggest that targeted therapy against DECR1 combined with further inhibition of its downstream pathway involving SLC7A11/GPX4 may represent a promising strategy for treating breast cancer.

Synthesis, biological evaluation, molecular docking and dynamic simulation of novel benzofuran derivatives as potential agents against Alzheimer's disease

We have synthesized novel benzofuran derivatives (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives showed inhibitory activities having IC50 values ranging from 0.70 ± 0.01 to 28.10 ± 0.50 µM (against AChE), while 0.80 ± 0.01 to 31.20 ± 0.60 µM (against BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 and 4.50 ± 0.10 µM, respectively). Except derivative 5, all other derivatives of the series showed good inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, but some analogues like 2, 4, 7, 14, 15, and 16 displayed many folds better inhibitory activity than the standard drug donepezil. The influences of substituents on inhibitory activity were superficially resonated via the structure-activity relationship. We established molecular docking and MD simulation studies to confirm the binding interaction between potent derivatives and active sites of enzymes.