AutoDock Tools Research Articles

Molecular Docking Study of Ferulic Acid Analog Compounds as Lung Antifibrotic at TGF-β1 Receptors

Pulmonary fibrosis is one of the conditions that occur in Post-COVID Syndrome patients. Development of specific treatment as an agent to treat pulmonary fibrosis is still ongoing. Ferulic acid is a compound that has a potential lung antifibrotic agent through inhibition of TGF-β1-mediated signaling. Molecular docking studies using the AutoDock Tools program version 1.5.7 were conducted on ferulic acid and its analogs to determine the activity of compounds as antifibrotic. Furthermore, the interaction of the compound with the receptor was visualized using the Discovery Studio 2021 program. The results showed that ferulic acid and its analogs have lower free energy than pirphenidone which is a standard lung antifibrotic drug. 4- benzoyloxy-3-methoxycinnamic acid is the compound that has the greatest activity. The group that contributes to the ligand-receptor interaction is the aromatic group with π interaction. Keywords: Molecular docking, AutoDock, antifibrotic, TGF-β1, ferulic acid

Potencial of Ursolic Acid Derivatives as Anti Breast Cancer

Breast cancer is one of the biggest contributors to death in the world. Several treatment methods such as chemotherapy, hormonal therapy, radiation therapy, and surgery have shown side effects and resistance to breast cancer. Bioactive compounds are now an alternative in the development of drugs for breast cancer. Pearl grass is one of the plants reported to contain bioactive compounds that have inhibitory activity against breast cancer cells, namely ursolic acid. Most reports describe modifications of groups on its structure increasing the potential of ursolic acid as a breast cancer drug. This study aims to develop breast cancer drugs with raw materials of ursolic acid derivative compounds that are modified on the active side with groups that play an important role as anticancer using the Quantitative Structure and Activity Relationship (QSAR) method and molecular docking. The QSAR descriptors used are hydrophobic, steric, and electronic. The characters of each descriptor were computed using the SwissADME, Molinspiration, and NWChem programs with the DFT method, B3LYP function, and 6-31G* basis set. Molecular docking was performed using the AutoDock Tools 1.5.6 program and visualized using the Biovia Studio Visualizer program. The results showed that the regression coefficient (R2) of the QSAR model had a high correlation of 0.985 with the compound (1S,2R,4aS,6aR,6bR,10S,12aR,12bR,14bS)-10-amino-1,2,6a,6b,9,9, 12a-heptamethyl-14-oxoicosahydropicene-4a(2H)-carboxylic acid became the best compound validated by the results of molecular docking which has a binding energy of -7.92 kcal/mol and an inhibition constant of 1.42 nM so that it can inhibit MCF-7 cells in breast cancer.

Design, synthesis and anti-Tb evaluation of chalcone derivatives as novel inhibitors of InhA

A series of halogenated chalcone derivatives were designed and developed for anti-tubercular activity. Novel molecules were designed and in-silico screening were performed using admetSAR, SwissADME, and Osiris Property Explorer. From the initial filter the top 10 compounds were docked using the Autodock tool 1.5.6. and the binding energies of the docked compounds were higher than the standard drugs Isoniazid.and Ethionamide. Based on the in-silico and docking results, the top halogenated chalcones were synthesized and characterized using FT-IR, mass spectrometry, 1H, and 13C NMR spectroscopy. The chalcones were further evaluated for anti-tubercular activity using MABA against the H37Rv strain. Among the series of compounds, DK12 and DK14 showed potent in-vitro activity, with MICs of 0.8 µg/ml, in comparison with 1.6 µg/ml of the first-line drug Isoniazid. Further molecular dynamics simulations studies for 100 ns revealed that the key interaction with TYR 158 were observed in both DK12 and DK14 in the InhA active site. The compound DK12 further showed significant interactions with PHE 149 and ARG 153 residues and is a hit molecule among the series. Further DK12 and DK14 does not show any significance toxicity. The compounds DK12 needs to be optimized and further investigation to be carried out against InhA. Communicated by Ramaswamy H. Sarma

Quercetin's antibiofilm effectiveness against drug resistant Staphylococcus aureus and its validation by in silico modeling

Staphylococcus aureus is typically treated with antibiotics, however, due to its widespread and unselective usage, resistant strains of S. aureus have increased to a great extent. Treatment failure and recurring staphylococcal infections are also brought on by biofilm development, which boosts an organism's ability to withstand antibiotics and is thought to be a virulence factor in patients. The present study investigates the antibiofilm activity of naturally available polyphenol Quercetin against drug-resistant S. aureus. Micro dilution plating and tube adhesion methods were performed to evaluate the antibiofilm activity of quercetin against S. aureus. Quercetin treatment resulted in remarkably reduction of biofilm in S. aureus cells. Further we performed a study to investigate binding efficacies of quercetin with genes icaB and icaC from ica locus involved in biofilm formation. 3D structure of icaB, icaC and quercetin were retrieved from Protein data bank and PubChem chemical compound database, respectively. All computational simulation were carried out using AutoDock Vina and AutoDockTools (ADT) v 1.5.4. In silico study demonstrated a strong complex formation, large binding constants (Kb) and low free binding energy (ΔG) between quercetin and icaB (Kb = 1.63 × 10−5, ΔG = −7.2 k cal/mol) and icaC (Kb = 1.98 × 10−6, ΔG = −8.7 kcal/mol). This in silico analysis indicates that quercetin is capable of targeting icaB and icaC proteins which are essential for biofilm formation in S. aureus. Our study highlighted the antibiofilm activity of quercetin against drug resistant pathogen S.aureus.

Hecogenin a Plant Derived Small Molecule as an Antagonist to BACE-1: A Potential Target for Neurodegenerative Disorders.

The field of drug discovery has recognized the significance of computer-aided drug design. Recent advancements in structure identification and characterization, bio-computational science and molecular biology have significantly contributed to the development of novel treatments for various diseases. Alzheimer's disease is prevalent in over 50 million affected people, with the pathological condition of amyloidal plaque formation by the beta-amyloidal peptide that results in lesions of the patient's brain, thus making the target prediction and treatment a hurdle. In this study, we evaluated the potential of 54 bioactive compounds from Justicia adhatoda L. and Sida cordifolia L. identified through LC-MS/MS against the β-site amyloid precursor cleaving enzyme (beta-secretase) that results in the formation of amyloidal plaques. To study the drug-likeness of the phytocompounds, Lipinski's rule of five for ADME profiling and toxicity prediction was performed. Molecular docking was performed using auto-dock tool of PyRx software; molecular dynamic simulations were performed using the Schrodinger suite. Molecular docking against BACE-1 protein revealed that hecogenin, identified from S. cordifolia has a broad spectrum of pharmacological applications and a binding affinity score of -11.3 kcal/Mol. The Hecogenin-BACE-1 protein complex was found to be stable after 30 ns of MD simulation, resulting in its substantial stability. Further studies focusing on the in vivo neuroprotective activity of hecogenin against the disease will pave the way for efficient drug discovery from natural sources in a precise manner.

Use of network pharmacology and molecular docking to explore the mechanism of action of curcuma in the treatment of osteosarcoma

Curcuma has been used as an adjuvant treatment for osteosarcoma (OS) due to its anticancer compounds. However, the underlying mechanism remains unclear. Therefore, this study aimed to explore the mechanism of action of curcuma in the treatment of OS using network pharmacology and molecular docking. In this study, anticancer compounds were obtained from relevant literature, and curcuma-related targets and OS treatment targets were obtained from public databases. Protein‒protein interaction networks were constructed to screen out the hub genes using the STRING database and Cytoscape software. Cluster analysis of the protein modules was then performed using the Cytoscape MCODE plugin. Furthermore, Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed for common targets among curcuma targets and OS-related targets using the DAVID database. Finally, molecular docking was performed, and the results were verified by Auto dock Tool and PyMOL software. Our research identified 11 potential active compounds, 141 potential therapeutic targets and 14 hub genes for curcuma. AKT1, TNF, STAT3, EGFR, and HSP90AA1 were the key targets closely related to the PI3K/Akt signaling pathways, HIF-1 signaling pathways, ErbB signaling pathways, and FOXO signaling pathways, which are involved in angiogenesis, cancer cell proliferation, metastasis, invasion, and chemotherapy resistance in the microenvironment of OS. Molecular docking suggested that the core compound had a strong affinity for key targets, with a binding energy of less than – 5 kJ/mol. The study showed that curcuma-mediated treatment of OS was a complex process involving multiple compounds, targets, and pathways. This study will enhance the understanding of how curcuma affects the proliferation and invasion of OS cells and reveal the potential molecular mechanism underlying the effect of curcuma on OS lung metastasis and chemotherapy resistance.

In silico study of aminothiazole, benzohydrazide, namoline, piridine, and parnate derivatives as Jumonji domain histone lysine demethylase (KDM1A, KDM4A, KDM4C, KDM4E, AND KDM5B) inhibitors in prostate cancer

Background: Prostate cancer is the second most common type of cancer in men. The histone lysine demethylase enzyme is believed to be one of the genetic factors that cause prostate cancer. Based on in vivo testing, a group of compounds from the aminothiazole, benzohydrazide, pyridine, namoline, and parnate classes have been experimentally proven to be inhibitors of the histone lysine demethylase enzyme. Objective: This study aimed to investigate the interaction of 20 compounds consisting of aminothiazole, benzohydrazide, pyridine, namoline, and parnate derivatives with histone lysine demethylase enzymes (KDM1A, KDM4A, KDM4C, KDM4E, and KDM5B) in silico. Method: Molecular docking was performed using Autodock Tools v.4.2.3 to obtain the affinity of test compounds against the target molecule. This was followed by molecular dynamics (MD) simulation of some test compounds with the lowest inhibition constant using Gromacs software. Toxicity prediction was conducted to predict the safety of the test compounds. Result: The docking results revealed the top five compounds for each receptor with the lowest inhibition constant and free binding energy value (∆G), suggesting the best affinity to histone lysine demethylase enzymes. The results from MD showed that the compounds with the codes aminothiazole, pyridine, parnate 1, parnate 2, and parnate 5 were stable when bound to the KDM1A receptor. The toxicity test results also indicated that the test compounds were safe and had a low health risk, as they were neither genotoxic nor non-genotoxic carcinogens. Conclusion: Based on the research results, it can be concluded that compounds with the codes aminothiazole, pyridine, parnate 1, parnate 2, and parnate 5 can serve as inhibitors of histone lysine demethylase enzymes on the KDM1A receptor and are stable when bound to the receptor.

The Potency of Alkaloid Derivates as Anti-Breast Cancer Candidates: In Silico Study

Breast cancer is the most frequent malignancy in women worldwide. One of the target receptors for the treatment of breast cancer are estrogen, progesterone, and HER2 receptors. An alternative treatment using natural ingredients has been developed, one of which is alkaloid compounds. This study aims to determine the activity of alkaloid compounds as anti-breast cancer agents through an in-silico method. Virtual screening (AutoDock Vina), molecular docking (AutoDock Tools), molecular dynamics (Desmond), scanning Lipinski's rule of five, as well as pharmacokinetic and toxicity parameters, were performed. The results of virtual screening, molecular docking, and molecular dynamics show that the compounds daurisoline, solasodine, and sambutoxin have stable interactions with the HER2 receptor, with the lowest values of RMSD (Root Mean Square Deviation) and RMSF (Root Mean Square Fluctuation) compared to other compounds. Based on the results of the study conducted, it was shown that daurisoline, solasodine, and sambutoxin were predicted to be used as anti-HER2 candidates for the treatment of breast cancer.

Integrated analysis of diagnostic, prognostic value and potential drug treatment of GSDME in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) poses a global health challenge. Effective biomarkers for early detection are necessary to improve the survival rate of HNSC patient. The purpose of this study was using integrated bioinformatic analysis to investigate the potential biological roles of GSDME in HNSC. The Gene Expression Omnibus (GEO) and Cancer Gnome Atlas (TCGA) databases were used to analyze the expression of GSDME in different cancer types. The correlation between GSDME expression and immune cell infiltration or immune checkpoint genes was examined by Spearman correlation analysis. DNA methylation analysis of the GSDME gene was conducted using the MethSurv database. Kaplan-Meier (K-M) survival curves, diagnostic receiver operating characteristic (ROC) curves, nomogram model, and Cox regression analysis were chosen to evaluate the diagnostic and prognostic predictive value of GSDME. Connectivity Map (Cmap) online platform, Protein Data Bank (PDB) database and Chem3D, AutoDock Tool and PyMol software were used to predict and visualize potential molecular drugs aimed for GSDME. GSDME expression level in HNSC was significantly higher than in the controls (p < 0.001). Differentially expressed genes (DEGs) correlation with GSDME were enriched in the GO pathways, such as protein activation cascade, complement activation and classical pathway (p < 0.05). According to GSEA, GSDME-associated differentially expressed genes were significantly enriched in KRAS signaling pathway and cytokine signaling molecule (p < 0.05). There is a significant relation between GSDME expression and immune cell infiltration in HNSC tissues, as well as immune checkpoint genes expression (p < 0.001). DNA methylation status of cg17790129 CpG islands of GSDME gene is correlated with HNSC prognosis (p < 0.05). Based on Cox regression analysis of HNSC patients, GSDME as a potential risk gene has high correlation with overall survival (OS) and disease specific survival (DSS) (p < 0.05). In a ROC curve analysis, HNSC tissues were differentiated from adjacent peritumoral tissues based on GSDME expression levels (AUC = 0.928). Totally six potential drugs targeted for GSDME were screened and the molecular docking tests between GSDME protein and candidate drugs were conducted. GSDME is a promising therapeutic target as well as a potential clinical biomarker in HNSC patients.

Structure of molecule, density gradient, orbital locator and reactivity of 5,6-dichloro-1-cyclopentyl-2-(methylsulfinyl)-1H-benzimidazole- potent inhibitor of map kinase

The present work consists of theoretical studies with the DFT technique on the benzo[d]imidazole derivative, 5,6-Dichloro-1-cyclopentyl-2-(methylsulfinyl)-1H-benzimidazole, and its biological evaluation in silico. The molecule is subjected to geometry optimisation and further DFT studies in gas and solvent phases. Upon solvation with polar solvents, gradual variation in properties result. Topological analyses are performed using Multiwfn software (ELF, LOL, RDG and charge transfer) to illustrate the electron density distribution, interactions, and excitation within the title molecule. ADMETLab 2.0, PreADMET, and SwissADME online tools compute the ADMET profile. Select MAP-kinase target proteins are docked against the title molecule using AutoDock Tools and PyMOL. Discovery Studio Visualizer software is run for visualisation and result analysis of the docked ligand-protein complex.

Repurposing of drugs against methyltransferase as potential Zika virus therapies

In recent years, the outbreak of infectious disease caused by Zika Virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Several possible druggable targets involved in virus replication have been identified. In search of additional potential inhibitors, we screened 2895 FDA-approved compounds using Non-Structural Protein 5 (NS5) as a target utilizing virtual screening of in-silco methods. The top 28 compounds with the threshold of binding energy −7.2 kcal/mol value were selected and were cross-docked on the three-dimensional structure of NS5 using AutoDock Tools. Of the 2895 compounds screened, five compounds (Ceforanide, Squanavir, Amcinonide, Cefpiramide, and Olmesartan_Medoxomil) ranked highest based on filtering of having the least negative interactions with the NS5 and were selected for Molecular Dynamic Simulations (MDS) studies. Various parameters such as RMSD, RMSF, Rg, SASA, PCA and binding free energy were calculated to validate the binding of compounds to the target, ZIKV-NS5. The binding free energy was found to be −114.53, −182.01, −168.19, −91.16, −122.56, and −150.65 kJ mol−1 for NS5-SFG, NS5-Ceforanide, NS5-Squanavir, NS5-Amcinonide, NS5-Cefpiramide, and NS5-Ol_Me complexes respectively. The binding energy calculations suggested Cefpiramide and Olmesartan_Medoxomil (Ol_Me) as the most stable compounds for binding to NS5, indicating a strong rationale for their use as lead compounds for development of ZIKV inhibitors. As these drugs have been evaluated on pharmacokinetics and pharmacodynamics parameters only, in vitro and in vivo testing and their impact on Zika viral cell culture may suggest their clinical trials on ZIKV patients.

Integration of Network Pharmacology and Molecular Docking to Analyse the Mechanism of Action of Oregano Essential Oil in the Treatment of Bovine Mastitis.

The active components, potential targets, and mechanisms of action of oregano essential oil in the treatment of bovine mastitis disease were investigated using network pharmacology and molecular docking approaches. The TCMSP and literature databases were examined for the main compounds in oregano essential oil. Afterward, the physical, chemical, and bioavailability characteristics of the components were evaluated. The PubChem, BATMAN, PharmMapper, and Uniprot databases were utilized to predict the target genes of the major components of oregano essential oil. Via the databases of DrugBank, OMIM, GeneCards, TTD, and DisGenet, the disease targets of bovine mastitis were discovered. We analyzed common targets and built protein-protein interaction (PPI) networks using the STRING database. Key genes were analyzed, obtained, and compound-target-pathway-disease visualization networks were created using Cytoscape. For the GO function and KEGG pathway enrichment analysis, the DAVID database was utilized. Molecular docking via Autodock Tools was utilized to evaluate the reliability of the interactions between oregano essential oil and hub targets. Thymol, carvacrol, and p-cymene are the three major components found in oregano essential oil. The potential targets (TNF, TLR4, ALB, IL-1β, TLR2, IL-6, IFNG, and MyD88) were screened according to the visual network. The enrichment analysis suggested that the major signaling pathways in network pharmacology may include PI3K-Akt, MAPK, IL-17, and NF-κ B. Molecular docking analysis shows that thymol had good docking activity with TNF, IL-6, and MyD88, carvacrol had good docking activity with TNF, and p-cymene had good docking activity with ALB. This study clarified the mechanism of action of oregano essential oil in the treatment of bovine mastitis, thus providing data supporting the potential for the use of oregano essential oil in the development of new therapeutics for bovine mastitis.

Potential pharmacological mechanisms of four active compounds of Macleaya cordata extract against enteritis based on network pharmacology and molecular docking technology.

Background: Macleaya cordata extract (MCE) is effective in the treatment of enteritis, but its mechanism has not been fully elucidated. Therefore, this study combined network pharmacology and molecular docking technologies to investigate the potential pharmacological mechanism of MCE in the treatment of enteritis. Methods: The information of active compounds in MCE was accessed through the literature. Furthermore, PubChem, PharmMapper, UniProt, and GeneCards databases were used to analyze the targets of MCE and enteritis. The intersection of drug and disease targets was imported into the STRING database, and the analysis results were imported into Cytoscape 3.7.1 software to construct a protein-protein interaction (PPI) network and to screen core targets. The Metascape database was used for conducting Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. AutoDock Tools software was used for the molecular docking of active compounds with the core targets. Results: MCE has four active compounds, namely, sanguinarine, chelerythrine, protopine, and allocryptopine, and a total of 269 targets after de-duplication. Furthermore, a total of 1,237 targets were associated with enteritis, 70 of which were obtained by aiding the drug-disease intersection with the aforementioned four active compound targets of MCE. Five core targets including mitogen-activated protein kinase 1 (MAPK1) and AKT serine/threonine kinase 1 (AKT1) were obtained using the PPI network, which are considered the potential targets for the four active compounds of MCE in the treatment of enteritis. The GO enrichment analysis involved 749 biological processes, 47 cellular components, and 64 molecular functions. The KEGG pathway enrichment analysis revealed 142 pathways involved in the treatment of enteritis by the four active compounds of MCE, among which PI3K-Akt and MAPK signaling pathways were the most important pathways. The results of molecular docking showed that the four active compounds demonstrated good binding properties at the five core targets. Conclusion: The pharmacological effects of the four active compounds of MCE in the treatment of enteritis involve acting on signaling pathways such as PI3K-Akt and MAPK through key targets such as AKT1 and MAPK1, thus providing new indications for further research to verify its mechanisms.

PENAMBATAN MOLEKUL SIANIDIN Ipomoea batatas L. SEBAGAI INHIBITOR HUMAN EPIDERMAL RECEPTOR 2 (HER-2) PADA KANKER PAYUDARA

HER-2 (Human Epidermal Receptor 2) is a receptor on the cell surface that affects cell proliferation, this receptor support controls healthy cell growth,divide and repair cells when they are damaged. When HER-2 had overexpressed will not controlled cancer cell division. Overexpressed HER-2 could inhibited with cyanidine compound flavonoid derivatives from Ipomoea batatas L. (purple sweet potato). This study aim to measured potential of Ipomoea batatas L. cyanidin compounds in inhibited overexpressed HER-2 using computational chemistry methods specifically is molecular docking. Stages of molecular docking receptor HER-2 is ligand set up with drew structure cyanidine with Marvin Sketch then optimized by Autodock Tools and Discovery Studio, lapatinib as a comparison ligand downloaded on PubChem website. HER-2 (3PP0) prepared with downloaded on Protein Data Bank website then optimized by Autodock Tools. Molecular Docking validated with docked protein target with native ligand by PyMOL to secured RMSD (root mean square deviation). Protein Targeted HER-2 docked with test ligand cyanidine, lapatinib, and native ligand by Autodock VINA, analysed energy bond and amino acid residue interactions by LigPlot+. Cyanidine had potency inhibitor of receptor HER-2 overexpressed from docked is had bound energy -7.1 ccal/mol up to -8.6 ccal/mol wich is also had amino acid residue interactions Met 801 equal to native ligand

Network Pharmacology and Molecular Docking Analysis of Active Compounds in Tualang Honey against Atherosclerosis.

Atherosclerosis, a pathological condition marked by the accumulation of lipids and fibrous substances in the arterial walls, is a leading cause of heart failure and death. The present study aimed to utilize network pharmacology to assess the potential pharmacological effects of bioactive compounds in Tualang honey on atherosclerosis. This is significant as previous studies have indicated the cardioprotective effects of Tualang honey, yet a comprehensive evaluation using network pharmacology has yet to be conducted. The bioactive compounds in Tualang honey were screened and the potential gene targets for these compounds were predicted through Swiss Target Prediction and SuperPred databases. Atherosclerosis genes were retrieved from the OMIM, DisGeNet, and GeneCards databases. The interaction between these compounds and atherosclerosis genes was established through protein-protein interaction, gene ontology, and KEGG pathway analysis. The results of these analyses were then further confirmed through molecular docking studies using the AutoDock Tools software. The results revealed that 6 out of 103 compounds in Tualang honey met the screening criteria, with a total of 336 potential gene targets, 238 of which were shared with atherosclerosis. Further analysis showed that these active compounds had a good affinity with key targets and were associated with biological processes related to protein phosphorylation and inflammation as well as pathways related to lipid and atherosclerosis and other signaling pathways. In conclusion, the study provides insight into the potential pharmacological effects of Tualang honey bioactive compounds on atherosclerosis, supporting its use as a promising treatment for the disease.

Selection and Molecular Response of AHL-lactonase (aiiA) Producing Bacillus sp. Under Penicillin G-induced Conditions.

Quorum sensing (QS) is the process by which microorganisms employ chemicals called autoinducers (AIs) to communicate with their population. The QS mechanism generally controls the expression of the virulence related genes in bacteria. N-acyl homoserine lactones (AHLs) are the most widespread QS molecules. Due to their diverse AHL-lactonase activities, Bacillus species make particularly suitable candidates for procedures such as demolition of pathogenic bacterial QS signals and bioremediation of β-lactam antibiotics from contaminated environments. In this study, seven Bacillus strains with Quorum quenching (QQ) activity were isolated using an enrichment medium supplemented with Penicillin G (PenG). The AHL-lactonase encoding gene (aiiA) was amplified by PCR and sequenced. Amino acid sequences underwent multiple sequence alignment. Docking studies were carried out with both C6HSL and PenG ligand using AutoDock tools. The aiiA amino acid sequences of the isolates were found to be well conserved. Furthermore, amino acid sequence alignment revealed that 74.9% of amino acid sequences were conserved in the genus Bacillus. Docking of the C6HSL to wild type (3DHA) and H97D variant reduced the docking score by only 0.1kcal/mol for the mutated protein. When PenG docked with a higher (1.5kcal/mol) score as a ligand to wild-type and mutant receptors, the docking score for the mutated protein likewise decreased by 0.1kcal/mol. This research contributed to the diversification of organisms with QQ activity and beta-lactam antibiotic resistance. It also clarified the binding score of the PenG ligand to the Bacillus AHL lactonase molecule for the first time.

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer's Disease: Prospects for Designing New Therapeutics Compound.

Memory impairment is a result of multiple factors including amyloid-beta (Aβ) accumulation. Several receptors are mediated for Aβ transport and signaling. Moreover, blood lipids are involved in Aβ signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aβ signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83Å for RMSD along with -114.27, -107.44, and -122.51kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aβ. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer's disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood-brain barrier (BBB).

Are Non-Structural Proteins From SARS-CoV-2 the Target of Hydroxychloroquine? An in Silico Study

COVID-19 is caused by SARS-CoV-2 which has structural and non-structural proteins (NSP) essential for infection and viral replication. There is a possible binding of SARS-CoV-2 to the beta-1 chain of hemoglobin in red blood cells and thus, decreasing the oxygen transport capacity. Since hydroxychloroquine (HCQ) can accumulate in red cells, there is a chance of interaction of this drug with the virus. To analyze possible interactions between SARS-CoV-2 NSP and hemoglobin with the HCQ using molecular docking and implications for the infected host. This research consisted of a study using bioinformatics tools. The files of the protein structures and HCQ were prepared using the AutoDock Tools software. These files were used to perform molecular docking simulations by AutoDock Vina. The binding affinity report of the generated conformers was analyzed using PyMol software, as well as the chemical bonds formed. The results showed that HCQ is capable of interacting with both SARS-CoV-2 NSP and human hemoglobin. The HCQ/NSP3 conformer, HCQ/NSP5, HCQ/NSP7-NSP8-NSP12, HCQ/NSP9, HCQ/NSP10-NSP16 showed binding affinity. In addition, the interaction between HCQ and hemoglobin resulted in polar bonds. Interaction between SARS-CoV-2 NSP and HCQ indicates that this drug possibly acts by preventing the continuity of infection.

Flavonoids as Strong Inhibitors of MAPK3: A Computational Drug Discovery Approach.

Mitogen-activated protein kinase 3 (MAPK3) mediates the onset, progression, metastasis, drug resistance, and poor prognosis in various malignancies, including glioma, liver, ovarian, thyroid, lung, breast, gastric, and oral cancers. Negative regulation of MAPK3 expression using miRNAs has led to therapeutic effects in cancer. The present study performed molecular docking and dynamics simulation to identify potential MAPK3 inhibitors from natural flavonoids, possibly leading to drug development in cancer therapy. A computational drug discovery approach was performed using the AutoDock tool to identify potential MAPK3 inhibitors from 46 plant-based flavonoids. A cross-validation study was executed using the Schrödinger Maestro docking tool. Molecular dynamics (MD) was executed to evaluate the stability of docked poses between the top-ranked compounds and the MAPK3 catalytic domain. Interactions among the most potent MAPK3 inhibitors and residues within the receptor's active site were studied using the BIOVIA Discovery Studio Visualizer before and after 100 ns MD simulations. Kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 exhibited a magnificent binding affinity to the receptor's active site. In addition, the stability of the docked poses of these compounds seemed to be stable after ∼45 ns computer simulations. The present study suggests that kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 could strongly bind to the MAPK3 catalytic site and could be assigned as a potent inhibitor for MAPK3. These findings may be helpful in the treatment of various cancers. However, further validation experiments are needed.

Molecular interactions, binding stability, and synergistic inhibition on Acetylcholinesterase activity of Safranin O in combination with Quercetin and Gallic acid: In vitro and in silico study

The clinical management of multifactorial diseases, especially in neurodegenerative disorders, requires the identification of potent synergistic interactions between therapeutic molecules. In this context, the current study was carried out to evaluate the synergistic inhibitory effect on Acetylcholinesterase activity by Safranin O in combination with Quercetin and Gallic acid in vitro and in silico. Anti-AChE activity was assessed using Ellman's colorimetric method, while the Synergistic and antagonistic interactions were calculated by Loewe, Zip, Bliss and HSE statistical models and plotted using synergyfinder plus tool. Molecular docking of complexed ligands was performed by auto-dock vina tool, Discovery studio and MOE softwares. Molecular dynamic simulations were carried out using Desmond Schrödinger software and the essential parameters were analyzed in 100 ns of simulation time. Our results showed potent inhibitory activities for all tested compounds Safranin O (IC50=15.76±1.15 µM), Quercetin (IC50=21.41±0.25 µM), Gallic acid (IC50=77.59±0.44 µM) in comparison with Galantamine (IC50=2,14±0.07 µM). The binary combination (1/1 ratio) Exhibited a significant improvement in IC50 values, Safranine O - Quercetin (9.07±0.82 µM), Safranine O-Gallic acid (3.46±0.12 µM) and became statistically comparable to standard. The interactive dose-response matrixes and the interaction scores were developed and quantified; the latter showed potent synergistic forms in particular doses for each ligand. Moreover, in molecular docking analysis, Quercetin exhibited the highest binding energy (-10,7 Kcal/mol) followed by Safranin O (-9,3 Kcal/mol) and Gallic acid (-6,5 Kcal/mol) respectively in comparison with Reference drugs, Galantamine (-10,2 Kcal/mol), Donepezil (-10,5 Kcal/mol) and Rivastigmine (-7,5 Kcal/mol). In parallel, the studied ligands interacted with both PAS and CAS active site regions of AChE through different stable and strong interactions during molecular dynamic simulations. These findings appreciate the importance of the synergy approach to developing new potent combinations for A.D. management.