Docking Studies Research Articles

Computational assessment of the reactivity and anticancer activity of 1,2,3-triazole-thiazolidinones derivatives: An approach combining DFT calculations, molecular dynamics simulations, molecular docking, and ADMET

Cancer is a global health burden with escalating incidence and mortality rates, necessitating the exploration of novel therapeutic strategies. 1,2,3-Triazoles, recognized for their diverse biological activities, have emerged as attractive candidates in drug discovery targeting key proteins associated with various cancers. This study presents the synthesis of a library of 1,2,3-triazole hybrids incorporating thiazolidinone and isoxazoline moieties. The antitumor potential of these compounds was evaluated using both in-silico and in-vitro assays. Structure-activity relationship (SAR) analysis revealed that strategic substitution of the para position of the phenyl ring, particularly with a nitro (NO2) group, is promising to enhance cytotoxic activity. The binding potential of the synthesized compounds with the XIAP BIR2 domain, the specific receptor of caspase-3/7 activators, was explored through molecular docking. The stability of the protein-compound complexes procured from the docking was assessed through molecular dynamics (MD) simulation. The docking study demonstrated that the synthesized compounds had the potential to bind to the target protein. Among the compounds and their stereoisomers, compounds (R)-6d and (S)-6e exhibited a better binding potential to the protein. The MD simulation study revealed that the protein-(R)-6d complex was relatively stable.

In Silico Molecular Docking and Molecular Dynamics Analysis of Antimicrobial Triazole Derivatives: Insights from Synthesis, Computational and In Vitro Studies.

In the ongoing fight against bacterial resistance to antibiotics, this study focuses on synthesizing and evaluating 1,2,4-triazole derivatives to explore their potential as new antibacterial agents. 1,2,4-Triazole compounds are promising drug candidates with a wide range of therapeutic effects, including pain relief, antiseptic, antimicrobial, antioxidant, antiurease, anti-inflammatory, diuretic, anticancer, anticonvulsant, antidiabetic, and antimigraine properties. The structures of all the synthesized compounds were identified using their physicochemical properties and spectral techniques, such as IR and NMR. These compounds were then evaluated in molecular docking studies against antimicrobial activity in vitro and further supported by molecular dynamics studies. Compound 7, featuring a 6-chloro group on the phenyl ring, emerged as the most effective against Gram-positive S. aureus compared to the standard antibiotic ciprofloxacin. Docking studies revealed high and comparable affinities for all ten ligands, with compounds 4 and 6 showing the best-docked activity against Penicillin Acylase mutants. Further, compounds 6 and 10 displayed significant affinity against D-alanine-D-alanine ligase (DDL) from Yersinia pestis during 100 ns MD simulation. Notably, compound 7 demonstrated the highest binding score to the 5C1P protein, suggesting its potential as a lead molecule for the development of potent and safer antimicrobial agents. This research contributes valuable insights into addressing the escalating challenge of bacterial resistance.

Docking and Molecular Dynamics Studies on Anticancer Activities of Flavonoids as Inhibitors of CDK2 and CDK9

Docking and Molecular Dynamics Studies on Anticancer Activities of Flavonoids as Inhibitors of CDK2 and CDK9

Evaluation of 3, 3’-Disubstituted Oxindoles Derivatives as a Potential Anti- Cancer Tyrosine Kinase Inhibitors-molecular Docking and ADME Studies

Aim: This study aims to explore the binding interactions between synthesized 3,3’-Disubstituted Oxindoles and the HCK enzyme, with the specific goal of discovering potential anticancer agents. Background: Cancer presents an ongoing global health challenge, necessitating the exploration of innovative therapeutic approaches. Isatin derivatives and pyridine compounds hold great promise for the development of anticancer drugs due to their wide-ranging biological activities. Moreover, HCK plays a significant role in chemotherapy resistance and reduced drug efficacy in clinical settings, highlighting its importance in the intricate network of cancer pathophysiology. There is an urgent need for targeted interventions to regulate HCK activity and enhance cancer treatment outcomes. Methods: In our study, we ensured meticulous optimization of protein and ligand preparation to guarantee accurate docking simulations. We conducted molecular docking analyses using the state-of-the-art Glide module and assessed ADME properties using the Schrödinger suite's QikProp tool. Results: Through molecular docking, compounds 3c and 3e have emerged as promising anticancer agents with low docking scores against Tyrosine Kinase. Further ADME analysis has provided valuable insights into the compounds' in-silico behaviour, while computed dipole moments have enhanced our understanding of their physicochemical characteristics Conclusion: In this study, we explored how the synthesized compounds bind within the HCK active site, indicating potential anticancer properties. Through in silico docking, we identified compounds 3c and 3e as possible anticancer agents, with the lowest docking scores of -7.621 and -7.602 kcal/mol against Tyrosine Kinase. These findings emphasize the importance of computational approaches in drug discovery and offer valuable insights for future research and development efforts.

Deciphering the 4',7-dihydroxy-3'-methylflavone from Boerhavia, Agonist/Antagonist Interactions Against 5-HT2 Receptors using Homology Modeling, Molecular Docking, and Dynamic Simulation Studies.

Seizures, depression, and anxiety are neurological disorders that affected innumerable people worldwide. Recent research has revealed that targeting 5-hydroxytryptamine 2 (5-HT2) receptors can help suppress these conditions. An in-depth literature study has identified that phytocompounds from the Boerhavia genus could reduce seizures. Therefore, homology models of 5-HT2receptors were generated and validated using techniques such as the alignment of amino acid sequences and the Ramachandran plot. Later, a comparison of modeled structures was made with a non-redundant set of PDB structures. The pharmacokinetics, drug-likeness, blood-brain barrier (BBB) permeability, and Lipinski's rule of five shed light on 22 phytocompounds, which are the potential candidates for molecular docking among 127 Boerhavia's bioactive. Notably, molecular docking analysis revealed 4',7-dihydroxy-3'-methylflavone as the most potent lead compound, which has a strong binding affinity to all modeled receptors. Additionally, with a remarkably high docking score of -9.1 kcal/mol, 4',7-dihydroxy-3'-methylflavone showed promising interactions, particularly with 5-HT2A receptor, as seen from the RMSD, SASA, Rg, and number of hydrogen bonds during 100 ns molecular dynamic (MD) simulation. Principal component analysis (PCA) and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) further confirmed that 4',7-dihydroxy-3'-methylflavone is the best novel phytocompound in Boerhavia genus for 5-HT2 receptor as agonist/antagonist activity against seizures.

Mutational analysis reveals the importance of residues of the access tunnel inhibitor site to human P-glycoprotein (ABCB1)-mediated transport.

Human P-glycoprotein (P-gp) utilizes energy from ATP hydrolysis for the efflux of chemically dissimilar amphipathic small molecules and plays an important role in the development of resistance to chemotherapeutic agents in most cancers. Efforts to overcome drug resistance have focused on inhibiting P-gp-mediated drug efflux. Understanding the features distinguishing P-gp inhibitors from substrates is critical. Cryo-electron microscopy has revealed distinct binding patterns, emphasizing the role of the L-site or access tunnel in inhibition. We substituted 5-9 residues of the L-site with alanine to investigate whether the binding of a second inhibitor molecule to the L-site is required for inhibiting drug efflux. We reveal, for the first time, that mutations in the L-site affect the drug efflux activity of P-gp, despite their distance from the substrate-binding pocket (SBP). Surprisingly, after the mutations were introduced, inhibitors such as tariquidar and zosuquidar still inhibited drug efflux by mutant P-gps. Communication between the transmembrane helices (TMHs) and nucleotide-binding domains (NBDs) was evaluated using the ATPase assay, revealing distinct modulation patterns by inhibitors for the mutants, with zosuquidar exhibiting substrate-like stimulation of ATPase. Furthermore, L-site mutations abolished ATP-dependent thermal stabilization. In silico molecular docking studies corroborated the altered inhibitor binding due to mutations in the L-site residues, shedding light on their critical role in substrate transport and inhibitor interactions with P-gp. These findings suggest that inhibitors bind either to the SBP alone, and/or to alternate site(s) when the L-site is disabled by mutagenesis.

In-silico Studies and Antioxidant and Neuroprotective Assessment of Microencapsulated Celecoxib against Scopolamine-induced Alzheimer's Disease.

Alzheimer's Disease (AD) is an enervating and chronic progressive neurodegenerative disorder. Celecoxib (CXB) possesses efficacious antioxidants and has neuroprotective, anti- inflammatory, and immunomodulatory properties. However, the poor bioavailability of CXB limits its therapeutic utility. Thus, this study aimed to evaluate the microencapsulated celecoxib MCXB) for neuroprotection. CXB was screened by molecular docking study using AutoDock (version 5.2), and the following proteins, such as 4EY7, 2HM1, 2Z5X, and 1PBQ were selected for predicting its neuroprotective effect. Scopolamine 20 mg/kg/day for approximately 7 days was administered to albino rats. Pure CXB 100 mg/kg/- day and 200 mg/kg/day, and MCXB 100 mg/kg/day and 200 mg/kg/day were administered, respectively. Further, to assess the oxidative stress, the nitric oxide (NO), superoxide dismutase (SOD), catalase, and lipid peroxidation (LPO) were evaluated using chemical methods. The neurochemical biomarkers like AChE, glutamate, and dopamine were evaluated using the ELISA method. Further, the histopathology of brain cells was carried out to assess the neuro-regeneration and neurodegeneration of the neurons. There was a significant binding interaction of CXB (score -6.3, -6.5, -5.1, -9.1) and donepezil (score- 5.5, -7.6, -7.0, and -8.6) with AchE (4EY7), β-secretase (2HM1, monoamine oxidase (2Z5X), and glutamate (1PBQ), respectively. MCXB-treated rats (100 mg/kg/day, 200 mg/kg/day) showed increased SOD levels (p < 0.001), whereas NO, catalase, and LPO levels were significantly (p < 0.001) decreased as compared to scopolamine-treated rats. Further, MCXB-treated rats showed a modulatory effect in the level of dopamine and AchE. However, the glutamate level was significantly (p < 0.001) decreased. In addition to that, histopathological examination of the hippocampus part showed remarkable improvement in brain cells. So, the findings of the results revealed that MCXB, in a dose-dependent manner, showed a neuroprotective effect against scopolamine-induced AD. This effect may be attributed to the activation of cholinergic pathways.

Antimicrobial and Molecular Docking Studies of 1,3,4-Thiadiazole Tethered Sulfa-Azo Derivatives via Hydrazono-Methyl Bridge

A new series of 1,3,4-thiadiazole linked to sulfa-azo derivatives via hydrazono-methyl bridge were synthesized via the reaction of methyl ((E)-(sulfa-derivatives)diazenyl) benzylidene)hydrazine-1-carbodithioates 1a-e with ethyl ester and acetyl hydrazonyl halides 2a-d. The chemical structures of the newly 1,3,4-thiadiazoles 3a-t have been clarified considring their elemental and spectral analysis. Antimicrobial activity of the newly 1,3,4-thiadiazoles was determined for Staphylococcus aureus, Escherichia coli, Candida albicans, as well as Aspergillus niger using the cup agar plate diffusion method. Out of the twenty compounds, compounds 3j, 3k, 3l, and 3s with isoxazole sulfonamides were selected for MIC assay. Compound 3j was equipotent with neomycin control drug against all tested strains, while compound 3k was 4-fold higher than neomycin against S. aureus, E. coli, and C. albicans with MIC values of 9.77, 19.53, and 19.53 μg/mL, respectively. Compound 3l was equipotent with neomycin against S. aureus and C. albicans, while it was 2-fold higher than neomycin against E. coli with MIC of 39.06 μg/mL. For 3s, it was less potent than neomycin against all tested microbs with 2-fold and 4-fold less potent. Further scanning electron microscopy (SEM) investigation has been studied to reveal the disruption effect of the selected potent antimicrobial compound (3k) on the intact cells of tested microbs S. aureus, E. coli in addition to C. albicans. Results showed that 3k exhibited a noticeable effect on destroying microbial cell walls. Furthermore, molecular docking study has been done to assess the binding behavior of two most effective compounds 3k and 3l with the target crystal structure of dihydropteroate synthase (PDB: 6CLV for S. aureus) and (PDB: 5U14 for E. coli). Compound 3k was shown to be able to form stable complexes with both target enzymes of dihydropteroate synthase through hydrogen bonding and hydrophobic interactions.

Assessment of the Anti-Adipogenic Effect of Crateva religiosa Bark Extract for Molecular Regulation of Adipogenesis: In Silico and In vitro Approaches for Management of Hyperlipidemia Through the 3T3-L1 Cell Line.

This study aimed to determine the phytoconstituents of Crateva religiosa bark (CRB) and evaluate the hypolipidemic effect of bioactive CRB extract by preventing adipocyte differentiation and lipogenesis. After performing the preliminary phytochemicals screening, the antioxidant activity of CRB extracts was determined through a DPPH (2, 2-diphenyl-1-picrylhydrazyl) assay. Ethyl acetate extract (CREAE) and ethanol extract (CRETE) of CRB were selected for chromatographic evaluation. The antihyperlipidemic potential was analyzed by molecular docking through the PKCMS software platform. Further, a 3T3-L1 cell line study via In vitro sulforhodamine B assay and western blotting was performed to confirm the prevention of adipocyte differentiation and lipogenesis Results: The total phenolic contents in CREAE and CRETE were estimated as 29.47 and 81.19 μg/mg equivalent to gallic acid, respectively. The total flavonoid content was found to be 8.78 and 49.08 μg/mg, equivalent to quercetin in CREAE and CRETE, respectively. CRETE exhibited greater scavenging activity with the IC50 value of 61.05 μg/ mL. GC-MS analysis confirmed the presence of three bioactive molecules, stigmasterol, gamma sitosterol, and lupeol, in CRETE. Molecular docking studies predicted that the bioactive molecules interact with HMG-CoA reductase, PPARγ, and CCAAT/EBP, which are responsible for lipid metabolism. In vitro, Sulforhodamine B assays revealed that CRETE dose-dependently reduced cell differentiation and viability. Cellular staining using 'Oil Red O' revealed a decreased lipid content in the CRETE-treated cell lines. CRETE significantly inhibited the induction of PPARγ and CCAAT/EBP expression, as determined through protein expression via western blotting. The influence of CRETE on lipid metabolism in 3T3-L1 cells is potentially suggesting a new approach to managing hyperlipidemia.

Design, synthesis, in vitro bio-evaluation and in silico molecular docking study of benzohydrazide based thiourea analogues

A series of new benzohydrazide based thiourea derivatives were synthesized, characterized through different spectroscopic techniques like 1HNMR, 13CNMR and HREI-MS and screened against Bacillus pasteurii (B.P) and Jack bean (J.B) ureases enzymes. All derivatives showed good inhibitory potential ranging from 20.05 ± 0.03 to 39.34 ± 1.05 (against J.B Urease) and 23.54 ± 0.21 to 58.65 ± 0.41 (against B.P Urease) as compared to the standard thiourea (IC50 = 14.02 ± 0.25 and 18.01 ± 0.13 µM, respectively). It was observed that the two scaffold 1 (IC50 = 23.54 ± 0.21 and 20.05 ± 0.03 µM) and 2 (IC50 = 26.20 ± 0.32 and 21.33 ± 0.17 µM) among the series showed good inhibitory potential. The binding interaction of the most potent analogues with the active site of enzyme were examined through the molecular docking study.

Engineering of Saccharomyces cerevisiae towards synthesis of linalool using linalool synthase from Magnolia champaca

Linalool is one of the commercially important fragrance molecule usually extracted from Lavandula angustifolia (lavender) and Ocimum basilicum (basil) plants. In the present study, efforts were made to produce this molecule in microbial system to meet demand-supply imbalance. Linalool synthase (LIS) gene from Magnolia champaca (Mc) and Coriandrum sativum (Cs) were successfully cloned and expressed in Saccharomyces cerevisiae CEN PK2–1 C. It was observed that expression of full-length LIS (fLIS) resulted in lesser linalool when compared to truncated LIS (tLIS) devoid of plastid signal for both Mc and Cs. In terms of linalool yield, MctLIS resulted in 1.27-fold higher linalool when compared to CstLIS. Later, when two more genes viz., TPI1 and ALD6 which presumably increase sterol pathway flux were overexpressed, actually resulted in lower linalool and increased acetate production. However, multicopy expression of MctLIS and tHMG1 in this strain has reversed the above phenomenon due to presumptive push-pull strategy. Finally, this engineered strain was cultivated in the 2 L bioreactor in fed-batch mode to obtain 10.85 µg/mL of linalool. Docking studies of homology model of MctLIS with geranyl pyrophosophate (GPP) revealed V387, Y361, T434, R427 and R249 as key interactions sites. The study reports the linalool production using LIS gene from Magnolia champaca for the first time and could be a potential chassis for further studies.

Anti-Neuroinflammatory Potential of Areca Nut Extract and Its Bioactive Compounds in Anthracene-Induced BV-2 Microglial Cell Activation.

Particulate matter (PM2.5) containing polycyclic aromatic hydrocarbons (PAHs) is of considerable environmental importance worldwide due to its adverse effects on human health, which are associated with neurodegenerative diseases (NDDs). Areca catechu L. (AC) fruit is known to possess various pharmacological properties; however, the anti-neuroinflammatory roles of AC on the suppression of PAH-induced neuroinflammation are still limited. Thus, we focused on the effects and related signaling cascades of AC and its active compounds against anthracene-induced toxicity and inflammation in mouse microglial BV-2 cells. Phytochemicals in the ethanolic extract of AC (ACEE) were identified using LC-MS, and molecular docking was conducted to screen the interaction between compounds and target proteins. Significant bioactive compounds in ACEE such as arecoline, (-)-epicatechin, and syringic acid were evinced through the LC-MS spectrum. The docking study revealed that (-)-epicatechin showed the highest binding affinities against NF-κB. For cell-based approaches, anthracene induced intracellular ROS, mRNA levels of TNF-α, IL-1β, and IL-6, and the release of TNF-α through enhancing JNK, p38, and NF-κB signaling pathways. However, the co-treatment of cells with ACEE or (-)-epicatechin could reverse those anthracene-induced changes. The overall study suggested that ACEE-derived bioactive compounds such as (-)-epicatechin may be developed as a potential anti-neuroinflammatory agent by preventing inflammation-mediated NDDs.

Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer's Disease: Their Design, Synthesis, and In-Vitro and In-Silico Investigations.

Alzheimer's Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes. The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman's spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted. Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 μM, 0.096 μM, and 0.177 μM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied. Overall, this research contributes to the development of 1,3,4-oxadiazole- quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer's disease.

3,3’4-trimethoxy-4’-rutinosylellagic acid and its acetylated derivative: Antioxidant activity and antiproliferative effects on breast cancer cells and molecular docking study

Cancers account for many deaths worldwide and natural compounds and their derivatives are interesting chemotherapeutic agents for cancer drug development. In this study, a natural compound 3,3’4-trimethoxy-4’-rutinosylellagic acid (TR2) and its acetylated derivative 3,3’4-trimethoxy-4’-hexaacetylrutinosylellagic acid (TR22) were evaluated for their antioxidant and anticancer effects against estrogen sensitive (MCF-7) and estrogen non-sensitive (MDA-MB 231) breast adenocarcinoma. In the β-Carotene-linoleic acid assay, DPPH• radical scavenging and CUPRAC assay, the compound TR2 had better activity than the standard α-Tocopherol, while in the ABTS•+ assay, it was more active than both standards α- α-Tocopherol and BHA. Both compounds had good antioxidant effects with TR2 being more active than TR22. Both compounds inhibited growth of breast carcinoma cells when compared to the untreated controls after 72 h. Compound TR22 significantly (p < 0.001) inhibited proliferation of both MCF-7 and MDA-MB 231 breast carcinoma cell lines suggesting that acetylation reaction improves inhibition of breast cancer cells growth. On the contrary, TR2 exhibited better inhibitory effect of clone formation than TR22 suggesting that acetylation reduces the activity in this assay. Both compounds inhibited migration of the cancer cells when compared to the untreated control cells and compound TR2 exhibited greater cellular anti-migration effect than TR22 at the same concentration and after the same period of incubation. Molecular docking studies supplemented the results and revealed that TR2 and TR22 had appreciable interactions with tyrosine kinase with negative binding energies suggesting that they are potent receptor tyrosine kinase inhibitors which can impede on cancer progression.

Sedative and anxiolytic effects of Capparis sicula Duhamel: in vivo and in silico approaches with phytochemical profiling.

The World Health Organization reports that 30% of adults worldwide suffer from insomnia, while 10% of people worldwide suffer with various forms of anxiety. The significant negative effects of conventional medications used to treat anxiety and insomnia, such as abuse, addiction, amnesia, and cognitive and sexual dysfunction, have led to an increased preference for naturally derived substances with fewer side effects. Accordingly, in this study, the sedative and anxiolytic effects of n-hexane, ethyl acetate (EtOAc), methanol (MeOH) and water extracts of the aerial parts of Capparis sicula Duhamel., which is used for sedative purposes in folk medicine, were evaluated. To evaluate the sedative and anxiolytic effects of each extract, bioassay systems were used including traction and hole-board tests. The MeOH extract of C. sicula was the most active extract on in vivo traction and hole-board tests compared to Diazepam. From the MeOH extract, major components were isolated, and their structures were identified as three flavonoid glycosides [rutin (1), quercetin-3-O-glucoside (2), and quercetin 3-O-rhamnoside (3)] using spectral techniques. The most abundant component was determined to be rutin, comprising 8mg/100mg dry extract in MeOH extract and 76.7mg/100mg dry fraction in fraction C using HPLC. The molecular docking studies evaluated the interaction of isolated flavonoid glycosides with the interaction energies and protein-ligand interaction details of the anxiety-related receptors GABAA and GABAB. For the GABAA receptor, quercetin-3-O-glucoside demonstrated the highest docking score. Quercetin-3-O-rhamnoside and rutin also show promising interactions, particularly with the GABAB receptor, highlighting their potential as modulators of these receptors. In conclusion, the use of C. sicula for sedative purposes in folk medicine has been confirmed for the first time by in vivo studies, and its possible active compounds and sedative-anxiolytic mechanism have been determined through phytochemical and in silico studies.

Unravelling the physicochemical and antimicrobial mechanisms of human serum albumin/tannic acid coatings for medical-grade polycaprolactone scaffolds

Biofilm-related biomaterial infections are notoriously challenging to treat and can lead to chronic infection and persisting inflammation. To date, a large body of research can be reviewed for coatings which potentially prevent bacterial infection while promoting implant integration. Yet only a very small number has been translated from bench to bedside. This study provides an in-depth analysis of the stability, antibacterial mechanism, and biocompatibility of medical grade polycaprolactone (mPCL), coated with human serum albumin (HSA), the most abundant protein in blood plasma, and tannic acid (TA), a natural polyphenol with antibacterial properties. Molecular docking studies demonstrated that HSA and TA interact mainly through hydrogen-bonding, ionic and hydrophobic interactions, leading to smooth and regular assemblies. In vitro bacteria adhesion testing showed that coated scaffolds maintained their antimicrobial properties over 3 days by significantly reducing S. aureus colonization and biofilm formation. Notably, amplitude modulation-frequency modulation (AMFM) based viscoelasticity mapping and transmission electron microscopy (TEM) data suggested that HSA/TA-coatings cause morphological and mechanical changes on the outer cell membrane of S. aureus leading to membrane disruption and cell death while proving non-toxic to human primary cells. These results support this antibiotic-free approach as an effective and biocompatible strategy to prevent biofilm-related biomaterial infections.

Molecular docking studies and molecular dynamic simulation analysis: To identify novel ATP-competitive inhibition of Glycogen synthase kinase-3β for Alzheimer’s disease

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Developing New Peptides and Peptide-Drug Conjugates for Targeting the FGFR2 Receptor-Expressing Tumor Cells and 3D Spheroids.

In this work, we utilized a biomimetic approach for targeting KATO (III) tumor cells and 3D tumoroids. Specifically, the binding interactions of the bioactive short peptide sequences ACSAG (A-pep) and LPHVLTPEAGAT (L-pep) with the fibroblast growth factor receptor (FGFR2) kinase domain was investigated for the first time. Both peptides have been shown to be derived from natural resources previously. We then created a new fusion trimer peptide ACSAG-LPHVLTPEAGAT-GASCA (Trimer-pep) and investigated its binding interactions with the FGFR2 kinase domain in order to target the fibroblast growth factor receptor 2 (FGFR2), which is many overexpressed in tumor cells. Molecular docking and molecular dynamics simulation studies revealed critical interactions with the activation loop, hinge and glycine-rich loop regions of the FGFR2 kinase domain. To develop these peptides for drug delivery, DOX (Doxorubicin) conjugates of the peptides were created. Furthermore, the binding of the peptides with the kinase domain was further confirmed through surface plasmon resonance studies. Cell studies with gastric cancer cells (KATO III) revealed that the conjugates and the peptides induced higher cytotoxicity in the tumor cells compared to normal cells. Following confirmation of cytotoxicity against tumor cells, the ability of the conjugates and the peptides to penetrate 3D spheroids was investigated by evaluating their permeation in co-cultured spheroids grown with KATO (III) and colon tumor-associated fibroblasts (CAFs). Results demonstrated that Trimer-pep conjugated with DOX showed the highest permeation, while the ACSAG conjugate also demonstrated reasonable permeation of the drug. These results indicate that these peptides may be further explored and potentially utilized to create drug conjugates for targeting tumor cells expressing FGFR2 for developing therapeutics.

Exploring Juniperus phoenicea L extract through phytochemical analysis, anti-lipase effects, and comprehensive molecular studies

Lipase inhibitors are used in the treatment of candidiasis, obesity, and acne problems. Therefore, the investigation of new natural lipase inhibitors has generated great interest. Juniperus phoenicea is a small Mediterranean tree considered an important medicinal plant. Through this work, we investigated the composition and inhibition effect of J. phoenicea extract on Candida rugosa and human lipases; and we analyzed the interactions between detected compounds and lipases using molecular docking, ADME-T, and dynamic studies. We extracted the secondary metabolites from the plant aerial parts and tested their activities against lipase. We examined major components of J. phoenicea, using Autodock vina for molecular docking, Desmond from Schrodinger suite 2021–1 for dynamics, and evaluating its drug-likeness and toxicity properties using ADMET webserver. We found that the IC50 values of ethyl acetate and methanol extracts are 1.33±0.10 and 1.731 mg/mL. Using HPLC quantitative analysis we identified in ethyl acetate extract the following phenolic compounds gallic acid, rutin, apigenin-7-O-glucoside, cinnamic acid, and quercetin. The complex apigenin-7-O-glucoside-lipase is stabilized by four hydrogen bonds and hydrophobic interactions, and the binding energy equals -10 Kcal/mol, which is better than the interactions saved for orlistat. Dynamic Simulation demonstrated better stability in the ligand-protein complex apigenin-7-O-glucoside-1lpb within 100 ns than the orlistat-1lpb complex. This study is described in this work for the first time. The results indicated that apigenin-7-O-glucoside from J. phoenicea L could be a good choice to develop a new drug candidate against candidiasis, obesity, and other lipase-related diseases.

Investigating the Therapeutic Property of Galium verum L. (GV) for MSG induced Audiogenic Epilepsy (AEs) and Neuroprotection through In-Silico and In-Vitro Analysis.

Audiogenic Epilepsy (AEs) is a subtype of epileptic seizure that is generally caused by high-intensity sounds. A large number of traditional medicines has been explored in this lieu where our study chased Galium verum L. (Rubiaceae), an herbal plant which is commonly known as Lady's Bedstraw, that contains a highly rich chemical composition including flavonoids (Hispidulin, Quercetin, and Kaempferol), and phenolic acids (chlorogenic acid, caftaric acid, and gallic acid). G verum is well known for its antioxidant, neuroprotective, and anti-inflammatory properties. Recently, the unique role of Adhesion G Protein- Coupled Receptor V1 (ADGRV1) protein in the progression of audiogenic epilepsy has been explored. This study aimed to examine the potent phytoconstituents of the hydroalcoholic extract of G. verum L. (HEGV) using analytical techniques. Additionally, our study sought to evaluate the antioxidant, neuroprotective, anti-inflammatory properties, and antiepileptic potency of HEGV by targeting ADGRV1 via in silico and in vitro analyses using SHSY5Y cells. HPLC and LC-MS techniques were employed to identify the flavonoids, iridoids, and phenolic acid derivatives present in HEGV. DPPH (2,2-diphenyl-1-picrylhydrazyl), nitric oxide (NO), and hydroxyl (OH) radical scavenging assays were performed to confirm the antioxidant potential of the extract. Additionally, in silico molecular docking and molecular dynamic studies were performed using AutoDock Vina software to analyze the possible interactions between crucial phytoconstituents of HEGV and ADGRV1, followed by cell line analysis. In the in vitro analysis, antioxidant, neuroprotective, and anti-inflammatory properties were assessed via cell viability assay, IL, GABA, and glutamate estimation. LC-MS and HPLC analyses revealed high concentrations of hispidulin, a major flavonoid found in HEGV. HEGV exhibited moderate-to-high free radical-scavenging activities comparable to those of ascorbic acid. Docking analysis demonstrated that hispidulin has a stronger binding affinity with ADGRV1 (Vina score = -8.6 kcal/mol) than other compounds. Furthermore, cell line analysis revealed that the MSG exacerbates the neurodegeneration and neuroinflammation, whereas, HEGV and Hispidulin both possess neuroprotective, antioxidant, and antiepileptic activities. HEGV and Hispidulin proved to be promising candidates for treating audiogenic epilepsy by modulating ADGRV1.