scholarly journals Molecular docking studies of dihydropyridazin-3(2H)-one derivatives as Antifungal, antibacterial and anti-helmintic agents

2021 ◽  
Vol 12 (1) ◽  
pp. 186-214
Author(s):  
Manish Devgun ◽  
Sushil Prasad ◽  
SukhbirLal Khokra ◽  
Rakesh Narang

Molecular docking is the identification of ligand’s correct binding geometry i.e pose in the binding site and estimation of its binding affinity for the rational design of drug molecule. The current study endeavored the high throughput insilico screening of 24 compounds docked with their respective protein using PyRx-Virtual Screening Tool software. Out of 24 compounds, almost all test compounds showed a very good binding affinity score. Fluconazole was used as a standard drug in case of Antifungal, Ciprofloxacin in case of Antibacterial, and Albendazole in case of Antihelmintics. More negative is the binding free energy score, more favorable is the pose for binding to protein active site. Based on H-bond interactions of these 24 compounds, Compounds 3a5, 3c3, 3d5, 3d6 were found to be the similar outcome for antifungal activity as fluconazole, Compound3a1 for antibacterial, and Compounds 3b5, 3d6 for the antihelmintic agent. Furthermore, the affinity of any small ligand molecules can be considered as an extraordinary tool in the field of drug design and offer imminent in future examination to build up potent antimicrobial agents.

2021 ◽  
Vol 6 (4) ◽  
pp. 270-283
Author(s):  
Sushil Prasad ◽  
Sukhbir Lal Khokra ◽  
Manish Devgun

Molecular docking is the identification of ligand’s correct binding geometry i.e. pose in the binding site and estimation of its binding affinity for rational design of drug molecule. The current study endeavored the high throughput in silico screening of 56 derivatives of dihydropyridazin-3(2H)-one docked with human cytosolic branched chain amino transferase using PyRx-virtual screening tool. Out of 56 compounds, almost all the test compounds showed very good binding affinity score. Gabapentin was used as standard drug which shows binding affinity of -6.2. On the basis of H-bond interactions, compounds 3, 9, 11, 25, 26, 31, 34, 39, 47, 48, 51, 54, 56 were found to be potent outcome for anticonvulsant activity. Compounds 11, 25, 39, 56 showed excellent H-bond interactions with protein active site, Among which compound 11 showed the outstanding interactions with acceptable bond length 2.34, 2.57, 2.62, 3.03 Å.


Author(s):  
Alisha Khandelwal ◽  
Tripti Sharma

<p>In this research a dataset of plant based bioactive compound was developed. A total of 101 phytochemicals were selected, virtually designed and its binding affinity with ACE enzyme was studied by molecular docking. Human ACE related carboxypeptidase and complex (PDB ID: 1R42) and (PDB ID: 6CS2) were selected for molecular docking studies as corona virus binds to ACE2 to enter into the host cell. Docking score results revealed that almost all selected phytochemicals binds to the pocket of the human ACE protein with high binding affinity and the scores were compared with chloroquine and hydroxychloroquine. The drug likeliness and ADMET analysis of all the screened compounds were performed. Two potential compound 6-α-acetoxygedunin and echitamine exhibited optimum binding with both the receptor.These phytochemicals can serve as lead molecule for further optimization and drug development against COVID-19. Therefore, it is predicted that the insights in the present study could be regarded valuable towards development of natural inhibitor of this virus.</p>


2020 ◽  
Vol 22 (10) ◽  
pp. 716-727
Author(s):  
Malihe Akhavan ◽  
Naser Foroughifar ◽  
Hoda Pasdar ◽  
Ahmadreza Bekhradnia

Aim and Objective: The magic scaffolds rhodanine and thiazolidine are very important heterocyclic compounds in drug design and discovery. Those are important heterocyclic compounds that have attracted a great deal of attention due to the fact that they exhibit a variety of bioactivities including antibacterial, antifungal, antiviral, antimalarial, and anti-inflammatory activities. These agents often exhibit selective toxicity. The goal of this study was molecular docking, green and solvent-free efficient synthesis of a new series of hetero/aromatic substituted rhodanine and thiazolidine analogues and then investigation of their antimicrobial activity. Materials and Methods: To a mixture of TZD or rhodanine (1 mmol) in the presence of ionic liquid ChCl/urea, various aldehyde (1 mmol) was added. After completion of the reaction, obtained crude compound was collected by filtration and products were recrystallized from ethanol. The binding-free energy between all synthesized compounds with 3EEJ protein (C. glabrata enzyme) were obtained by molecular docking studies. These compounds were evaluated using microdilution method against (ATCC 6538) and (ATCC 12228) Gram-negative, (ATCC 8739) and (ATCC 9027) as Gram-positive and (ATCC 1012), (ATCC 339), C. (ATCC 1057), (ATCC 503), (ATCC 340) and (ATCC 194) as fungi. Results: All of the acceptable products were determined by 1H NMR, 13C NMR, Mas and FT-IR spectroscopy. The binding-free energy between compounds 10a and 10b with 3EEJ protein were found to be -8.08 kcal/mol and -8.15 kcal/mol, respectively. These compounds having a heteroaromatic ring attached to the TZD or rhodanine core showed excellent antimicrobial activity with MIC values of 0.25-8 μg/mL (compound 10a) and 0.5-16 μg/mL (compound 10b) against the most tested fungi strains, Gram-positive and Gram-negative bacteria. Conclusion: A convenient and rapid method has been developed for the synthesis of rhodanine and thiazolidine-2,4-dione (TZD) derivatives as efficient antimicrobial agents using a Deep Eutectic Ionic Liquids (DEILs) choline chloride urea under solvent-free condition. Among the newly synthesized compounds, (Z)-5-((quinoxalin-3-yl) methylene) thiazolidine-2, 4-dione (10a) and (Z)- 5- ((quinoxalin-3-yl) methylene)-2-thioxothiazolidin-one (10b) exerted the promising effect and these compounds can be considered to be further probed as inhibitors of cgDHFR enzyme.


2020 ◽  
Author(s):  
Alisha Khandelwal ◽  
Tripti Sharma

<p>In this research a dataset of plant based bioactive compound was developed. A total of 101 phytochemicals were selected, virtually designed and its binding affinity with ACE enzyme was studied by molecular docking. Human ACE related carboxypeptidase and complex (PDB ID: 1R42) and (PDB ID: 6CS2) were selected for molecular docking studies as corona virus binds to ACE2 to enter into the host cell. Docking score results revealed that almost all selected phytochemicals binds to the pocket of the human ACE protein with high binding affinity and the scores were compared with chloroquine and hydroxychloroquine. The drug likeliness and ADMET analysis of all the screened compounds were performed. Two potential compound 6-α-acetoxygedunin and echitamine exhibited optimum binding with both the receptor.These phytochemicals can serve as lead molecule for further optimization and drug development against COVID-19. Therefore, it is predicted that the insights in the present study could be regarded valuable towards development of natural inhibitor of this virus.</p>


2016 ◽  
Vol 3 (3) ◽  
pp. 1
Author(s):  
Fajeelath Fathima ◽  
Abitha Haridas ◽  
Baskar Lakshmanan

PPARs play crucial role in the regulation of cellular differentiation, development and metabolism of carbohydrates, lipids and proteins in human, of which PPAR- ? has pivotal role in glucose homeostasis. In modern drug designing, molecular docking is routinely used for understanding drug receptor interaction. In the present study molecular docking were performed on a diverse set of 3,5-disubstituted thiazolidinedione chalcone derivatives that demonstrate antidiabetic activity by stimulating PPAR- ?. Among the designed analogues, e3, a3, b3 and c3 showed significant binding free energy of -12.29, -12.04, -11.53 and -11.45 kcal/mol with predicted inhibitory constant values of 987.38 pM, 1.5, 3.53 and 4.04 nM respectively and all the selected compounds were compared with standard drug Rosiglitazone.


2018 ◽  
Vol 5 (2) ◽  
pp. 001-005
Author(s):  
H. A. Ahmed ◽  
I. Y. Alkali

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that regulate the gene expression of proteins involved in glucose, lipid metabolism, adipocyte proliferation and differentiation and insulin sensitivity. Thiazolidinediones (TZDs) are one important class of synthetic agonists of PPAR-γ. TZDs are antidiabetic agents that target adipose tissue and improve insulin sensitivity, and they are currently being used in the treatment of type 2 diabetes. The study was carried out in order to discover new phytochemicals that have the ability to stimulate the PPAR-γ using molecular docking studies. AutoDock vina was used as molecular-docking tool in order to carry out the docking simulations. Nine phytochemicals namely plumbagin, quercetin, isovitexin, mangiferin, syringin, lupe-20-ene-3-one, purine 2, 6-dione, diosmetin and β sitosterol and pioglitazone a standard drug were docked against PPAR-γ using AutoDock vina and the results were analyzed using binding affinity. The results revealed that the compounds have significant binding affinity towards the PPAR-γ comparable to pioglitazone the standard drug. Based on the findings of this study these phytochemicals can serve as source of antidiabetic drugs via the mechanism of inhibition of PPAR-γ.


2022 ◽  
Vol 8 ◽  
Author(s):  
Entesar A. Hassan ◽  
Ihsan A. Shehadi ◽  
Awatef M. Elmaghraby ◽  
Hadir M. Mostafa ◽  
Salem E. Zayed ◽  
...  

In the present study, a general approach for the synthesis of 1-(1H-indol-3-yl)-3,3-dimercaptoprop-2-en-1-one (1) and 5-(1H-indol-3-yl)-3H-1,2-dithiole-3-thione (2) was performed. They are currently used as efficient precursors for the synthesis of some new compounds bearing five- and/or six-membered heterocyclic moieties, e.g., chromenol (3, 4), 3,4-dihydroquinoline (7, 8) and thiopyran (10, 12)-based indole core. In addition, molecular docking studies were achieved, which showed that all the newly synthesized compounds are interacting with the active site region of the target enzymes, the targets UDP-N-acetylmuramatel-alanine ligase (MurC), and human lanosterol14α-demethylase, through hydrogen bonds and pi-stacked interactions. Among these docked ligand molecules, the compound (9) was found to have the minimum binding energy (−11.5 and −8.5 Kcal/mol) as compared to the standard drug ampicillin (−8.0 and −8.1 Kcal/mol) against the target enzymes UDP-N-acetylmuramatel-alanine ligase (MurC), and Human lanosterol14α-demethylase, respectively. Subsequently, all new synthesized analogues were screened for their antibacterial activities against Gram-positive (Bacillus subtilis), and Gram-negative bacteria (Escherichia coli), as well as for antifungal activities against Candida albicans and Aspergillus flavus. The obtained data suggest that the compounds exhibited good to excellent activity against bacterial and fungi strains. The compound (E)-2-(6-(1H-indole-3-carbonyl)-5-thioxotetrahydrothieno [3,2-b]furan-2(3H)-ylidene)-3-(1H-indol-3-yl)-3-oxopropanedithioic acid (9) showed a high binding affinity as well as an excellent biological activity. Therefore, it could serve as the lead for further optimization and to arrive at potential antimicrobial agent.


Author(s):  
SRAVANTHI SILIVERI ◽  
NAGARAJU BASHABOINA ◽  
HARINADHA BABU VAMARAJU ◽  
Shiva Raj

Objective: The main objective of this work was to design, synthesize and evaluate the novel pyrazoline incorporated 1,2,3-triazole benzene sulphonamides for cytotoxic and anti-gout activities also to perform Insilco molecular docking studies. Methods: Designed compounds were synthesized by condensation of different substituted chalcones (3a-i) with hydrazine hydrate and substituted phenylhydrazines. All the synthesized compounds were characterized on the basis of physical and spectral data. To predict the affinity and activity of the ligand molecule Libdock program was employed to generate different bioactive binding poses of designing molecules at the active site of protein Phosphatidylinositol 3-kinase (PI3Kα). Title compounds were evaluated for cytotoxic activity by using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and anti-gout activity by potassium oxonate induced assay. Results: All the synthesized compounds showed characteristic peaks in FTIR, 1H, 13C NMR and MASS spectral analysis. In molecular docking studies, compound 3i has shown good binding affinity to the active site of PI3Kα with a docking score of 145.031 and 4 hydrogen bonding interactions with least hepatotoxicity and good bioavailability when compared with that of reference ligand KKR exhibited a Libdock score of 88.35. Remaining compounds also have a good binding affinity with a minimum of 2 bonding interactions and having better absorption, distribution, metabolism, elimination and toxicity (ADMET) profile. The same compound (3i) exhibited the highest cytotoxic activity with an IC50 value of 4.54µg/ml. Compound 4d was evaluated for anti-inflammatory activity and it has significantly ameliorated against potassium oxonate induced gout in mice when compared with that of standard drug allopurinol due to its anti-inflammatory property. Conclusion: We designed and synthesized a novel series of title compounds in quantitative yields and performed docking studies. New derivatives have a good binding affinity towards PI3Kα enzyme, good bioavailability, least hepatotoxicity and significant cytotoxic activity.


Author(s):  
Suman Rohilla ◽  
Ranju Bansal ◽  
Puneet Chauhan ◽  
Sonja Kachler ◽  
Karl-Norbert Klotz

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.


2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Hadiza Abdulrahman Lawal ◽  
Adamu Uzairu ◽  
Sani Uba

Abstract Background Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics “drug-likeliness” properties of the new compounds before they could proceed to pre-clinical trials. Results The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of (R2) = 0.6715, (R2adj) = 0.61920, (Q2) = 0.5460 and (R2pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five. Conclusions The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line).


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