scholarly journals β‐caryophyllene Oxide and Trans-nerolidol Affect Enzyme Activity of CYP3A4 – In Vitro and In Silico Studies

2019 ◽  
pp. S51-S58
Author(s):  
A. ŠPIČÁKOVÁ ◽  
V. BAZGIER ◽  
L. SKÁLOVÁ ◽  
M. OTYEPKA ◽  
P. ANZENBACHER
Keyword(s):  
Drug Metabolism ◽  
Active Site ◽  
Liver Microsomes ◽  
Docking Study ◽  
Biologically Active ◽  
Caryophyllene Oxide ◽  
Molecular Docking Study ◽  
In Silico Studies ◽  
Inhibition Studies

Evaluation of possible interactions with enzymes of drug metabolism is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. Here, focus is given on interactions of three sesquiterpenes (β-caryophyllene oxide (CAO), trans-nerolidol (tNER) and farnesol (FAR)) with CYP3A4. To determine the CYP3A4 activity, specific substrates testosterone (TES) and midazolam (MDZ) were used. In human liver microsomes, the CAO inhibited the MDZ 1´-hydroxylation by mixed type inhibition and Ki 46.6 μM; TES 6-hydroxylation was inhibited more strongly by tNER by the same mechanism and with Ki of 32.5 μM. Results indicated a possibility of different mode of interaction of both compounds within the active site of CYP3A4 and this was why the molecular docking study was done. The docking experiments showed that the studied sesquiterpenes (CAO and tNER) bound to the CYP3A4 active site cause a significant decrease of binding affinity of substrates tested which corresponded well to the inhibition studies. The inhibition observed, however, most probably does not pose a real harm to microsomal drug metabolism as the levels of sesquiterpenes in plasma (assuming the use of these compounds as spices or flavoring additives) does not usually exceed micromolar range. Hence, the interaction of drugs metabolized by CYP3A4 with sesquiterpenes is less probable.

scholarly journals A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

Molecules ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 184 ◽  
Author(s):  
Anca-Maria Borcea ◽  
Gabriel Marc ◽  
Ioana Ionuț ◽  
Dan C. Vodnar ◽  
Laurian Vlase ◽  
...  
Keyword(s):  
In Silico ◽  
Docking Study ◽  
Biological Evaluation ◽  
Antifungal Drugs ◽  
Biologically Active ◽  
Molecular Docking Study ◽  
Candida Spp ◽  
In Silico Admet ◽  
In Silico Studies

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits.

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

2020 ◽  
Vol 16 (7) ◽  
pp. 892-902 ◽  
Author(s):  
Aida Iraji ◽  
Mahsima Khoshneviszadeh ◽  
Pegah Bakhshizadeh ◽  
Najmeh Edraki ◽  
Mehdi Khoshneviszadeh
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Competitive Inhibition ◽  
Docking Study ◽  
Biological Evaluation ◽  
Primary Response ◽  
Ratio Method ◽  
Molecular Docking Study ◽  
Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

Novel coumarin containing dithiocarbamate derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes

2020 ◽  
Vol 16 ◽  
Author(s):  
Marjan Mollazadeh ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Yousef Valizadeh ◽  
Afsaneh Zonouzi ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Active Site ◽  
Docking Study ◽  
Secondary Amines ◽  
Molecular Docking Study ◽  
Glucosidase Inhibitors ◽  
Dithiocarbamate Derivatives

Background: α-Glucosidase is a hydrolyze enzyme that plays a crucial role in degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in the carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained of reaction between 4-(bromomethyl)-7-methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound compete with substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Also, molecular docking study predicted that this compound as well interacted with α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for design potent α-glucosidase inhibitors for treatment of type 2 diabetes.

scholarly journals Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2291 ◽  
Author(s):  
David Malinak ◽  
Eugenie Nepovimova ◽  
Daniel Jun ◽  
Kamil Musilek ◽  
Kamil Kuca
Keyword(s):  
Molecular Docking ◽  
Molecular Modelling ◽  
Active Site ◽  
Molecular Design ◽  
Docking Study ◽  
The Novel ◽  
Molecular Docking Study ◽  
Causal Treatment ◽  
Modelling Study

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described.

scholarly journals Isoniazid-Isatin Hydrazone Derivatives: Synthesis, Antitubercular Activity and Molecular Docking Studies

2021 ◽  
Vol 18 (21) ◽  
pp. 39
Author(s):  
Mardi Santoso ◽  
Muhammad Riza Ghulam Fahmi ◽  
Yehezkiel Steven Kurniawan ◽  
Taslim Ersam ◽  
Sri Fatmawati ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Active Site ◽  
Antitubercular Activity ◽  
Docking Study ◽  
Positive Control ◽  
Tuberculosis H37rv ◽  
Molecular Docking Study

This study examined the synthesis of isoniazid-isatin hydrazone derivatives 5-7, followed by an investigation on the in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, and molecular docking. A yield of 81 - 92 % of these compounds was achieved, with structural characterization by spectroscopic methods (FTIR, NMR, HRMS). The in vitro antitubercular activity was evaluated against M. tuberculosis H37Rv, and the highest effect was observed in compound 7, with a minimum inhibitory concentration (MIC) of 0.017 mM, lower than rifampicin (MIC 0.048 mM), which served as the positive control. In addition, the molecular docking of 5-7 was performed to visualize the interaction of isoniazid-isatin hydrazone derivatives with the active site of InhA receptor, which was in agreement with the experimental data. The hydrogen bonding with Ser94 and pi-pi interaction with Phe41 and/or Phe97 on the InhA active site was pivotal for the antitubercular activity. HIGHLIGHTS Tuberculosis caused by Mycobacterium tuberculosis is one of the top ten leading causes of death globally The first and second lines of antituberculosis drugs are the prevalent treatment for this disease, but they show several drawbacks and are exacerbated by the occurrence of drug resistance The isoniazid-isatin hydrazone derivatives were designed through molecular hybridization and synthesized effectively and exhibited moderate to high activity against tuberculosis H37Rv Molecular docking study demonstrated that the hydrogen bonding with Ser94 and the pi-pi interaction with Phe41 and/or Phe97 are important for antitubercular activity GRAPHICAL ABSTRACT

scholarly journals DOCKING ANTIOXIDANT ACTIVITY ON HYDROXY (DIPHENYL) ACETICACID AND ITS DERIVATIVES

2017 ◽  
Vol 10 (7) ◽  
pp. 263 ◽  
Author(s):  
Sudha Rajendran ◽  
Nithya G ◽  
Brindha Devi P ◽  
Charles C Kanakam
Keyword(s):  
Antioxidant Activity ◽  
Active Site ◽  
Data Bank ◽  
Docking Study ◽  
Protein Crystal ◽  
Molecular Docking Study ◽  
Ligand Interaction ◽  
Active Site Pocket ◽  
Study Results

Objectives: The antioxidant activity of the synthesized compounds along with the standard compound for comparison is reported. There is comparison of binding analysis and the ligand interaction of the compound. Methods: The protein crystal structure complexed with 4-methyl-6-[2-(5-morpholin-4-ylpyridin-3-yl)ethyl]pyridin-2-amine inhibitor was selected from Protein Data Bank (5FVP) for our study. Results: The docking studies and structure-activity relationship reveals that the compound 2’-chloro-4-methoxy-3nitro benzilic acid after three different docking strategies reveals that the score was found to be higher compared with others.Conclusion: Based on the in vitro antioxidant results, the compounds synthesized were investigated for the molecular docking study to identify the amino acid interactions in the active site pocket of nitric oxide synthase enzyme. Based on the docking score results, all the compounds were oriented toward the active site pocket occupied by the cocrystallized ligand

SYNTHESIS AND INVESTIGATION OF ANTI-ACETYLCHOLINESTERASE ACTIVITY IN SILICO AND IN VITRO OF SOME CHALCONES

2012 ◽  
pp. 98-106
Author(s):  
Thai Son Tran ◽  
Khac Minh Thai ◽  
Thanh Dao Tran
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Condensation Reaction ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
The Elderly ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Ic50 Value

Background: Alzheimer is a major cause of dementia in the elderly and acetylcholinesterase inhibitors are used to treat the symptoms of this disease. Recently, chalcones have been reported as potential acetylcholinesterase inhibitors. Materials and methods: In this study, Claisen-Schmidt condensation reaction was applied to synthesize chalcones. Anti-acetylcholinesterase activity of these chalcones was determined by Ellman method. Molecular docking studies on acetylcholinesterase were performed to explain the interaction between these chalcone analogues and acetylcholinesterase active site at molecular level. Results: A total of twenty chalcones were synthesized and determined for in vitro anti-acetylcholinesterase activity. The results indicated that six compounds having IC50 value below 100 µM, three compounds having IC50 value in the range of 100 µM and 300 µM, the rest having IC50 value above 300 µM. Chalcone S17 (4’-amino-2-chlorochalcone) shows the strongest anti-acetylcholinesterase activity in the investigated group with IC50 value of 36.10 µM. In combination with the results of the in vitro anti-acetylcholinesterase activity, molecular docking study is used to explain the interaction between chalcone molecules and their active site, and the structure-activity relationship is abstracted. Conclusions: Our study indicated that the 2’-hydroxychalcones with halogen functional groups on B ring are strong acetylcholinesterase inhibitors. Chalcone S17 (4’-amino-2-chlorochalcone) could be considered as a potential lead compound for the development of new acetylcholinesterase inhibitors. Keywords: acetylcholinesterase, AChE, Alzheimer, chalcon, docking. Key words: A cetylcholinesterase, AChE, Alzheimer, chalcon, docking

scholarly journals Crystallography, in Silico Studies, and In Vitro Antifungal Studies of 2,4,5 Trisubstituted 1,2,3-Triazole Analogues

Antibiotics ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 350 ◽  
Author(s):  
Katharigatta N. Venugopala ◽  
Mohammed A. Khedr ◽  
Yarabahally R. Girish ◽  
Subhrajyoti Bhandary ◽  
Deepak Chopra ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Intermolecular Interactions ◽  
Docking Study ◽  
X Ray Diffraction ◽  
Molecular Docking Study ◽  
Fungal Strains ◽  
Highly Active ◽  
Diphenyltetrazolium Bromide ◽  
In Silico Studies

A series of 2,4,5 trisubstituted-1,2,3-triazole analogues have been screened for their antifungal activity against five fungal strains, Candida parapsilosis, Candida albicans, Candida tropicalis, Aspergillus niger, and Trichophyton rubrum, via a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) microdilution assay. Compounds GKV10, GKV11, and GKV15 emerged as promising antifungal agents against all the fungal strains used in the current study. One of the highly active antifungal compounds, GKV10, was selected for a single-crystal X-ray diffraction analysis to unequivocally establish its molecular structure, conformation, and to understand the presence of different intermolecular interactions in its crystal lattice. A cooperative synergy of the C-H···O, C-H···N, C-H···S, C-H···π, and π···π intermolecular interactions was present in the crystal structure, which contributed towards the overall stabilization of the lattice. A molecular docking study was conducted for all the test compounds against Candida albicans lanosterol-14α-demethylase (pdb = 5 tzl). The binding stability of the highly promising antifungal test compound, GKV15, from the series was then evaluated by molecular dynamics studies.

scholarly journals COUMARIN ANALOGUES AS A POTENTIAL INHIBITOR OF LEISHMANIASIS: A MULTI-TARGETING PROTEIN INHIBITION APPROACH BY MOLECULAR DOCKING

2019 ◽  
Author(s):  
Kapish Kapoor
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Active Compound ◽  
Active Site ◽  
Therapeutic Potential ◽  
Docking Study ◽  
Developed Countries ◽  
Molecular Docking Study

Leishmaniasis is one of the most dreadful diseases as a leading cause of death in most of the developed countries. In the given study molecular docking study was performed on the library of coumarin analogues as anti-leishmaniasis agents. Total 300 coumarins analogues were taken from Pubmed and were studied using a molecular docking study on trypanothione reductase from Leishmania infantum (PDB code: 2JK6 and 2P18) and Leishmania mexicana (PDB code: 3PP7). Molecular docking result revealed that most active compound COU-130 and COU-220 bind to the active site of the protein with amino acids present in the various proteins. In PDB 2JK6 the active compound binds to the amino acid thr-51 and ser-14 were binding to the active site, and in PDB 3PP7 the active compound binds amino acid thr-26 and in PDB 2P18 the active compound binds to the amino acid phe-219 and try-212. Further in vitro and in vivo study of selected coumarin analogues can be studied for their therapeutic potential in treating leishmaniasis.

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