scholarly journals MOLECULAR DOCKING STUDY ON 1-(3-(4-BENZYLPIPERAZIN-1-YL)PROPYL)-3,7-DIMETHYL-1H-PURINE-2,6(3H,7H)-DIONE AS AN ACETYLCHOLINESTERASE INHIBITOR

2018 ◽  
Vol 6 ◽  
pp. 898-903
Author(s):  
Maria Hristova ◽  
Mariyana Atanasova ◽  
Iva Valkova ◽  
Lilya Andonova ◽  
Irini Doytchinova ◽  
...  
Keyword(s):  
Active Site ◽  
Acetylcholinesterase Inhibitor ◽  
Docking Study ◽  
Binding Mode ◽  
New Drugs ◽  
Ache Inhibition ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Good Target ◽  
Catalytic Active Site

Acetylcholinesterase (AChE) is a good target in the design of new drugs for the treatment of Alzheimer’s disease. The currently known drugs -donepezil, galantamine and rivastignime- act as moderate AChE inhibitors. In the present study, we docked a newly synthesized arylpiperazine derivative 1-(3-(4-benzylpiperazin-1-yl)propyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (LA1) into rhAChE and identified its binding mode. The docking pose of the studied LA1 molecule depends of the protonated state of the nitrogen atom of the piperazine moiety where in the best scored poses, the xanthine moiety of LA1 is bound into the catalytic active site (CAS) of AChE, while the arylpiperazine fragment is placed into the peripheral binding site (PAS). The Ellman’s test confirmed the compound binding. LA1 has good permeability through the GIT and BBB assessed by PAMPA. LA1 is a prospective lead for AChE inhibition.

scholarly journals Putative Molecular Mechanisms of Neuroprotective Cerebrosides and Their Docking Studies on Acetyl Cholinesterase Enzyme Inhibition for the Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
SHAIK IBRAHIM KHALIVULLA ◽  
Kokkanti Mallikarjuna
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Enzyme Inhibition ◽  
Docking Study ◽  
Tau Proteins ◽  
World Health ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Catalytic Active Site

Abstract The Dementia disease is characterised by neuropsychiatric disturbances due to lack of proper synaptic communication between neurons causing the cognitive behavioural problems. The Alzheimer’s disease (AD) in elderly population is one of the several forms of Dementia. Recent data by World Health Organisation indicates that nearly 10 million people are getting dementia every year, of which 60-70% accounts for AD. The etiology of AD involves the formation of amyloid-β plaques and neurofibrillary Tau tangles in the brain resulting in the death of neural cells. There is no permanent solution for AD treatment, except the FDA approved drugs like galantamine, donepezil, rivastigmine and memantine that are normally associated with side effects. At this juncture, cerebrosides, the natural secondary metabolites identified from different taxa with potential neuroprotective effects offer a promising scope for the treatment of AD. In this paper, cerebrosides reported from all taxa are pooled up along with their functions and listed. The review of literature revealed that Cerebrosides can increase the cognitive functions by regulating or interacting with the N-methyl-d-aspartate (NMDA) calcium ion (Ca2+) channels at post-synaptic receptor; nitric oxide (NO); Bcl2, Bax, amyloid precursor (APP) and Tau proteins; brain-derived neurotrophic factor (BDNF) and cAMP- response element-binding proteins (CREB).This indicates that the Cerebrosides could be potential therapeutic agents for the protection of neurons involved in neurodegenerative disease like Alzheimer’s disease. The current neuroprotective drugs are AChE inhibitors; hence, in the present investigation, in silico molecular docking study on cerebrosides for the inhibition of AChE was assessed to find out their capacity to interact with an active catalytic site of AChE. The results of present investigation revealed that all 22 cerebrosides selected for this work interacted with catalytic active site of AChE measured in terms of Gibbs free binding energy. Of all the cerebrosides assessed, compound 6 exhibited strong interaction, followed by 15. This is the first report of molecular docking study on cerebrosides for AChE enzyme inhibition for treatment of Alzheimer’s disease. Nevertheless, detailed in vitro and in vivo, biochemical and molecular investigations are needed to bring them to useful form.

scholarly journals Plectrabarbene, a New Abietane Diterpene from Plectranthus barbatus Aerial Parts

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2365
Author(s):  
Nawal M. Al Musayeib ◽  
Musarat Amina ◽  
Gadah Abdulaziz Al-Hamoud ◽  
Gamal A. Mohamed ◽  
Sabrin R.M. Ibrahim ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Active Site ◽  
Docking Study ◽  
Inhibition Mechanism ◽  
Ache Inhibition ◽  
Molecular Docking Study ◽  
Spectral Techniques ◽  
Aerial Parts ◽  
Insight Into

A new abietane diterpene namely plectrabarbene (2), together with two known compounds: sugiol (1) and 11,14-dihydroxy-8,11,13-abietatrien-7-one (3) have been isolated from the aerial parts of Plectranthus barbatus Andr. (Labiatae). The structures of these compounds were determined by various spectral techniques (e.g., UV, IR, NMR, and FAB) and by comparison with the literature data. A molecular docking study of the isolated diterpenes (1–3) was performed with AChE to gain an insight into their AChE inhibition mechanism. The results of docking experiments revealed that the all tested compounds showed binding affinity at the active site of AchE in comparison to donepezil.

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 Back to Nature: Combating Candida albicans Biofilm, Phospholipase and Hemolysin Using Plant Essential Oils

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 81
Author(s):  
Ahmed M. El-Baz ◽  
Rasha A. Mosbah ◽  
Reham M. Goda ◽  
Basem Mansour ◽  
Taranum Sultana ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Essential Oils ◽  
Docking Study ◽  
New Drugs ◽  
Molecular Docking Study ◽  
Plant Essential Oils ◽  
Force Microscopy ◽  
Atomic Force ◽  
Afm Analysis ◽  
Phenotypic Methods

Candida albicans is the causative agent of fatal systemic candidiasis. Due to limitations of antifungals, new drugs are needed. The anti-virulence effect of plant essential oils (EOs) was evaluated against clinical C. albicans isolates including cinnamon, clove, jasmine and rosemary oils. Biofilm, phospholipase and hemolysin were assessed phenotypically. EOs were evaluated for their anti-virulence activity using phenotypic methods as well as scanning electron microscopy (SEM) and atomic force microscopy (AFM). Among the C. albicans isolates, biofilm, phospholipase and hemolysins were detected in 40.4, 86.5 and 78.8% of isolates, respectively. Jasmine oil showed the highest anti-biofilm activity followed by cinnamon, clove and rosemary oils. SEM and AFM analysis showed reduced adherence and roughness in the presence of EOs. For phospholipase, rosemary oil was the most inhibitory, followed by jasmine, cinnamon and clove oils, and for hemolysins, cinnamon had the highest inhibition followed by jasmine, rosemary and clove oils. A molecular docking study revealed major EO constituents as promising inhibitors of the Als3 adhesive protein, with the highest binding for eugenol, followed by 1,8-cineole, 2-phenylthiolane and cinnamaldehyde. In conclusion, EOs have a promising inhibitory impact on Candida biofilm, phospholipase and hemolysin production, hence EOs could be used as potential antifungals that impact virulence factors.

Evaluation of the Anticancer and DNA-Binding Characteristics of Dichloro(diimine)zinc(II) Complexes

Chemistry ◽  
2021 ◽  
Vol 3 (4) ◽  
pp. 1178-1188
Author(s):  
Bandar A. Babgi ◽  
Doaa Domyati ◽  
Magda H. Abdellattif ◽  
Mostafa A. Hussien
Keyword(s):  
Dna Binding ◽  
Binding Constants ◽  
Docking Study ◽  
Binding Mode ◽  
Molecular Docking Study ◽  
Binding Characteristics ◽  
Anticancer Properties ◽  
Amino Phenol ◽  
Donor Acceptor ◽  
Diimine Complexes

Several metal diimine complexes have been reported to possess anticancer properties. To evaluate the anticancer properties of tetrahedral zinc(II) diimine complexes, six complexes were synthesized with the general formula M(N^N)Cl2 {where M = Zn, Pt and N^N = 2,2’-biquinoline (1), 2,2’-dipyridylketone (2) and 4-((pyridine-2-ylmethylene)amino)phenol (3)}. In general, the intrinsic DNA-binding constants for the different compounds exhibited values within close proximity; the changes in the viscosity of the CT-DNA upon binding to the compounds suggest intercalation-binding mode. Molecular docking study predicted that complexes containing the highly planar ligand 2,2’-biquinoline are capable to establish π–π interactions with nucleobases of the DNA; the other four complexes engaged in donor–acceptor interactions with DNA nucleobases. The six complexes and two reference drugs (cisplatin and sunitinib) were tested against two cancer cell lines (COLO 205 and RCC-PR) and one normal cell line (LLC-MK2), highlighting the better performance of the zinc(II) complexes compared to their platinum(II) analogues. Moreover, zinc(II) complexes have higher selectivity index values than the reference drugs, with promising anticancer properties.

scholarly journals Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2540 ◽  
Author(s):  
Wenhao Wu ◽  
Xintong Liang ◽  
Guoquan Xie ◽  
Langdi Chen ◽  
Weixiong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Docking Study ◽  
High Concentration ◽  
Molecular Docking Study ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Ic50 Values ◽  
Targeted Inhibitors ◽  
Further Development

A series of novel ligustrazine derivatives 8a–r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer’s disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 × 106; for 8r, IC50 BuChE/IC50 AChE = 1.32 × 107). Of note, 8q and 8r also presented potent inhibitory activities against Aβ aggregation, with IC50 values of 17.36 µM and 49.14 µM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 μM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest.

scholarly journals Molecular Docking Study of the Potential Relevance of the Natural Compounds Isoflavone and Myricetin to COVID-19

2021 ◽  
Vol 25 (3) ◽  
pp. 271-282
Author(s):  
Didik Priyandoko ◽  
◽  
Wahyu Widowati ◽  
Mawar Subangkit ◽  
Diana Jasaputra ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
Active Sites ◽  
Docking Study ◽  
Binding Mode ◽  
Molecular Docking Study ◽  
Wuhan City ◽  
The World ◽  
Novel Coronavirus ◽  
Proteins Interactions

The 2019 novel coronavirus (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly from its origin in Wuhan City, Hubei Province, China, to the rest of the world. The efficacy of herbal treatment in the control of contagious disease was demonstrated during the 2003 outbreak of severe acute respiratory syndrome (SARS). Natural compound used for this study were isoflavone and myricetin. Molecular docking was performed to analyze binding mode of the compounds towards 12 proteins related to COVID-19. The prediction shows that isoflavone and myricetin have moderate probability of antiviral activity. All of the docked compounds occupied the active sites of the proteins related to COVID-19. Based on QSAR and molecular docking, interactions were predicted with 10 out of 12 potential COVID-19 proteins for myricetin and with 9 out of 12 proteins interactions for isoflavone. A potential disease alleviating action is suggested for isoflavone and myricetin in the context of COVID-19 infection.

scholarly journals Structural Basis for the Inhibition of RNase H Activity of HIV-1 Reverse Transcriptase by RNase H Active Site-Directed Inhibitors

2010 ◽  
Vol 84 (15) ◽  
pp. 7625-7633 ◽  
Author(s):  
Hua-Poo Su ◽  
Youwei Yan ◽  
G. Sridhar Prasad ◽  
Robert F. Smith ◽  
Christopher L. Daniels ◽  
...  
Keyword(s):  
Active Site ◽  
Thermal Denaturation ◽  
Binding Mode ◽  
Rnase H ◽  
New Drugs ◽  
Structural Basis ◽  
Independent Manner ◽  
Approved Drugs ◽  
Hiv 1 ◽  
Rapid Emergence

ABSTRACT HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.

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