Bruguiera gymnorhiza (L.) Lam. at the Forefront of Pharma to Confront Zika Virus and Microbial Infections—An In Vitro and In Silico Perspective

The recent emergence of Zika virus (ZIKV) in Brazil and the increasing resistance developed by pathogenic bacteria to nearly all existing antibiotics should be taken as a wakeup call for the international authority as this represents a risk for global public health. The lack of antiviral drugs and effective antibiotics on the market triggers the need to search for safe therapeutics from medicinal plants to fight viral and microbial infections. In the present study, we investigated whether a mangrove plant, Bruguiera gymnorhiza (L.) Lam. (B. gymnorhiza) collected in Mauritius, possesses antimicrobial and antibiotic potentiating abilities and exerts anti-ZIKV activity at non-cytotoxic doses. Microorganisms Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae ATCC 70603, methicillin-resistant Staphylococcus aureus ATCC 43300 (MRSA), Salmonella enteritidis ATCC 13076, Sarcina lutea ATCC 9341, Proteus mirabilis ATCC 25933, Bacillus cereus ATCC 11778 and Candida albicans ATCC 26555 were used to evaluate the antimicrobial properties. Ciprofloxacin, chloramphenicol and streptomycin antibiotics were used for assessing antibiotic potentiating activity. ZIKVMC-MR766NIID (ZIKVGFP) was used for assessing anti-ZIKV activity. In silico docking (Autodock 4) and ADME (SwissADME) analyses were performed on collected data. Antimicrobial results revealed that Bruguiera twig ethyl acetate (BTE) was the most potent extract inhibiting the growth of all nine microbes tested, with minimum inhibitory concentrations ranging from 0.19–0.39 mg/mL. BTE showed partial synergy effects against MRSA and Pseudomonas aeruginosa when applied in combination with streptomycin and ciprofloxacin, respectively. By using a recombinant ZIKV-expressing reporter GFP protein, we identified both Bruguiera root aqueous and Bruguiera fruit aqueous extracts as potent inhibitors of ZIKV infection in human epithelial A549 cells. The mechanisms by which such extracts prevented ZIKV infection are linked to the inability of the virus to bind to the host cell surface. In silico docking showed that ZIKV E protein, which is involved in cell receptor binding, could be a target for cryptochlorogenic acid, a chemical compound identified in B. gymnorhiza. From ADME results, cryptochlorogenic acid is predicted to be not orally bioavailable because it is too polar. Scientific data collected in this present work can open a new avenue for the development of potential inhibitors from B. gymnorhiza to fight ZIKV and microbial infections in the future.

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In silico construction of a multiepitope Zika virus vaccine using immunoinformatics tools

Scientific Reports ◽

10.1038/s41598-021-03990-6 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Ana Clara Barbosa Antonelli ◽

Vinnycius Pereira Almeida ◽

Fernanda Oliveira Feitosa de Castro ◽

Jacyelle Medeiros Silva ◽

Irmtraut Araci Hoffmann Pfrimer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Zika Virus ◽

In Silico ◽

Protein Domain ◽

Effective Vaccine ◽

T Cell Epitopes ◽

Zikv Infection ◽

Acute Neuropathy

AbstractZika virus (ZIKV) is an arbovirus from the Flaviviridae family and Flavivirus genus. Neurological events have been associated with ZIKV-infected individuals, such as Guillain-Barré syndrome, an autoimmune acute neuropathy that causes nerve demyelination and can induce paralysis. With the increase of ZIKV infection incidence in 2015, malformation and microcephaly cases in newborns have grown considerably, which suggested congenital transmission. Therefore, the development of an effective vaccine against ZIKV became an urgent need. Live attenuated vaccines present some theoretical risks for administration in pregnant women. Thus, we developed an in silico multiepitope vaccine against ZIKV. All structural and non-structural proteins were investigated using immunoinformatics tools designed for the prediction of CD4 + and CD8 + T cell epitopes. We selected 13 CD8 + and 12 CD4 + T cell epitopes considering parameters such as binding affinity to HLA class I and II molecules, promiscuity based on the number of different HLA alleles that bind to the epitopes, and immunogenicity. ZIKV Envelope protein domain III (EDIII) was added to the vaccine construct, creating a hybrid protein domain-multiepitope vaccine. Three high scoring continuous and two discontinuous B cell epitopes were found in EDIII. Aiming to increase the candidate vaccine antigenicity even further, we tested secondary and tertiary structures and physicochemical parameters of the vaccine conjugated to four different protein adjuvants: flagellin, 50S ribosomal protein L7/L12, heparin-binding hemagglutinin, or RS09 synthetic peptide. The addition of the flagellin adjuvant increased the vaccine's predicted antigenicity. In silico predictions revealed that the protein is a probable antigen, non-allergenic and predicted to be stable. The vaccine’s average population coverage is estimated to be 87.86%, which indicates it can be administered worldwide. Peripheral Blood Mononuclear Cells (PBMC) of individuals with previous ZIKV infection were tested for cytokine production in response to the pool of CD4 and CD8 ZIKV peptide selected. CD4 + and CD8 + T cells showed significant production of IFN-γ upon stimulation and IL-2 production was also detected by CD8 + T cells, which indicated the potential of our peptides to be recognized by specific T cells and induce immune response. In conclusion, we developed an in silico universal vaccine predicted to induce broad and high-coverage cellular and humoral immune responses against ZIKV, which can be a good candidate for posterior in vivo validation.

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Assessment of the Pharmacological Properties and Phytochemical Profile of Bruguiera gymnorhiza (L.) Lam Using In Vitro Studies, In Silico Docking, and Multivariate Analysis

Biomolecules ◽

10.3390/biom10050731 ◽

2020 ◽

Vol 10 (5) ◽

pp. 731 ◽

Cited By ~ 4

Author(s):

Nabeelah Bibi Sadeer ◽

Kouadio Ibrahime Sinan ◽

Zoltán Cziáky ◽

József Jekő ◽

Gokhan Zengin ◽

...

Keyword(s):

Multivariate Analysis ◽

In Silico ◽

Biological Activities ◽

Radical Scavenging ◽

Total Phenolic ◽

Docking Analysis ◽

In Silico Docking ◽

Bruguiera Gymnorhiza ◽

Phytochemical Profile

Bruguiera gymnorhiza (L.) Lam. is claimed to effectively manage a number of ailments including diabetes and associated complications. Nonetheless, no attempt has been made to delineate its pharmacological propensities and phytochemical profile. This study was designed to appraise the antioxidant and enzymatic inhibitory properties relevant to the management of diabetes mellitus, obesity, and neurodegenerative and skin disorders. A combination of colorimetric assays and ultra-high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) were applied for the phytochemical screening of leaf, root, twig, and fruit extracts (methanol and ethyl acetate). In vitro antioxidant evaluations were via radical scavenging abilities (DPPH, ABTS), reducing potential (FRAP, CUPRAC), chelating power, and total antioxidant capacity (phosphomolybdenum). Seven key metabolic enzymes (α-amylase, α-glucosidase, tyrosinase, elastase, lipase, AChE, and BChE) were targeted to determine the inhibitory effects. Multivariate and in silico docking analysis were performed on collected data. Methanolic fruit extract yielded the highest total phenolic, tannin, and triterpenoid contents (174.18 ± 4.27 mg GAE/g, 176.24 ± 3.10 mg CE/g, 63.11 ± 3.27 mg OAE/g, respectively); significantly depressed tyrosinase, elastase, and α-amylase activities (155.35 ± 0.29 mg KAE/g, 4.56 ± 0.10 mg CAE/g, 1.00 ± 0.05 mmol ACAE/g, accordingly); and harboured the most potent antioxidant capacities with DPPH, CUPRAC, FRAP (492.62 ± 5.31, 961.46 ± 11.18, 552.49 ± 8.71 mg TE/g, respectively), and phosphomolybdenum (4.17 ± 0.31 mmol TE/g) assays. Multivariate analysis suggested that the type of solvents used influenced the biological activities more compared to plant parts. Docking analysis showed that azelaic acid binds with tyrosinase by Van der Waals and conventional hydrogen bonds. We anticipate that the present study may establish baseline data on this halophyte that could open new avenues for the development of biomedicine.

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In Silico Docking of Traditional Chinese Medicine Compounds and Novel Redesigned Ligands to Pseudomonas aeruginosa Quinolone Signaling Proteins PqsA and PqsD

10.1109/bibm52615.2021.9669881 ◽

2021 ◽

Author(s):

Natasha Danielle Sachiko L. De Guzman ◽

Jose Alfonso C. Madrono ◽

Marla A. Endriga ◽

Enrique Jose L. Frio

Keyword(s):

Pseudomonas Aeruginosa ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

In Silico ◽

Signaling Proteins ◽

In Silico Docking

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Antiviral Effect of Crude Aqueous Extracts from Ten Philippine Medicinal Plants against Zika Virus

Acta Medica Philippina ◽

10.47895/amp.v54i2.1501 ◽

2020 ◽

Vol 54 (2) ◽

Author(s):

Fatima Ericka S. Vista ◽

Leslie Michelle M. Dalmacio ◽

Laarni Grace M. Corales ◽

Gielenny M. Salem ◽

Jedhan U. Galula ◽

...

Keyword(s):

Medicinal Plants ◽

Antiviral Activity ◽

Zika Virus ◽

In Silico ◽

Therapeutic Index ◽

Antiviral Effect ◽

Viral Envelope ◽

Aqueous Extracts ◽

Plant Metabolites ◽

In Silico Docking

Objective. This study aimed to determine the antiviral activity of ten Philippine medicinal plants against Zika virus (ZIKV). Methods. Lyophilized aqueous plant extracts were used for cell cytotoxicity and virus inhibition assays. The therapeutic index was computed from the 50% cytotoxic concentration (CC50) and 50% effective concentration (EC50) values. Plant metabolites were also identified using mass spectroscopy. An in-silico screening of these metabolites was done using ZIKV enzymes and the Axl protein in human microglial cells as target proteins, followed by the ranking of binding energy scores to generate a hypothesis on the possible mechanism of antiviral action.Results. The plants that demonstrated the highest therapeutic index were Momordica charantia, Psidium guajava, Vitex negundo, and Blumea balsamifera. The majority of the metabolites present in the aqueous extracts were saponin, terpenes and terpenoids, and anthocyanin. Further, in-silico docking results showed a higher binding affinity for viral replication proteins compared to the viral envelope protein.Conclusion. The crude aqueous extracts of M. charantia, P. guajava, V. negundo, and B. balsamifera were the most potent candidate antiviral therapies against ZIKV among the ten plants tested. Meanwhile, the in-silico results suggested that the metabolites possibly employ an intracellular mechanism for the observed antiviral activity.

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Identifikasi Mekanisme Molekuler Senyawa Ftalosianina sebagai Kandidat Photosensitizer pada Terapi Fotodinamika secara In Silico

ALCHEMY Jurnal Penelitian Kimia ◽

10.20961/alchemy.17.1.41184.37-42 ◽

2021 ◽

Vol 17 (1) ◽

pp. 37

Author(s):

Taufik Muhammad Fakih ◽

Anggi Arumsari ◽

Mentari Luthfika Dewi ◽

Nurfadillah Hazar ◽

Tanisa Maghfira Syarza

Keyword(s):

Pseudomonas Aeruginosa ◽

Photodynamic Therapy ◽

Mechanism Of Action ◽

In Silico ◽

Pathogenic Bacteria ◽

Docking Study ◽

Protein Docking ◽

Atomic Contact ◽

Study Results ◽

Autodock 4.2

Bakteri patogen seperti Pseudomonas aeruginosa membutuhkan zat besi untuk dapat mempertahankan kelangsungan hidupnya. HasAp merupakan suatu protein yang dihasilkan oleh bakteri patogen sebagai sumber zat besi tersebut. Protein HasAp selanjutnya akan berikatan dengan protein membran luar yaitu HasR untuk dapat meneruskan sinyal pada sel bakteri. Penyerapan zat besi pada bakteri patogen ini dapat menjadi strategi pengembangan metode terapi dalam mengendalikan dan mencegah penyakit infeksi yang disebabkan oleh bakteri patogen Pseudomonas aeruginosa, salah satunya dengan memanfaatkan ftalosianina sebagai photosensitizer pada terapi fotodinamika. Penelitian ini bertujuan untuk mengidentifikasi, mengevaluasi, dan mengeksplorasi mekanisme aksi senyawa ftalosianina terhadap protein HasAp, serta pengaruhnya pada bagian sisi aktif HasR dengan menggunakan studi in silico. Studi ligan-protein docking dilakukan dengan menggunakan perangkat lunak MGLTools 1.5.6 yang dilengkapi dengan AutoDock 4.2 untuk mengamati afinitas dan interaksi molekuler antara molekul senyawa Fe-ftalosianina (Fe-Pc) dan Ga-ftalosianina (Ga-Pc) terhadap makromolekul protein HasAp. Selanjutnya, studi protein-protein docking dilakukan terhadap sistem kompleks ligan-protein untuk mengamati pengaruhnya terhadap area pengikatan dari makromolekul protein HasR dengan menggunakan perangkat lunak PatchDock. Berdasarkan hasil ligan-protein docking, senyawa Fe-ftalosianina (Fe-Pc) memiliki afinitas paling baik terhadap kedua protein HasAp, yaitu dengan nilai masing-masing -68,45 kJ/mol dan -69,16 kJ/mol. Kemudian, hasil studi protein-protein docking antara kompleks senyawa Fe-ftalosianina (Fe-Pc) dan protein HasAp terhadap protein HasR memiliki nilai Atomic Contact Energy (ACE) positif, yaitu 556,56 kJ/mol. Perbedaan struktur molekul senyawa ftalosianina terbukti mampu mempengaruhi mekanisme aksi terhadap protein target, sehingga hasil studi ini dapat menjadi acuan dalam mendesain struktur senyawa ftalosianina sebagai kandidat photosensitizer dalam terapi fotodinamika.Identification of the Molecular Mechanism of Phthalocyanine Compounds as Photosensitizer Candidates in Photodynamic Therapy by In Silico. Pathogenic bacteria including Pseudomonas aeruginosa need iron elements to be able to maintain their survival. HasAp is a protein produced by pathogenic bacteria as a source of iron. The HasAp protein will then bind to the outer membrane protein, namely HasR, to be able to forward signals in bacterial cells. Absorption of iron in these pathogenic bacteria can be a strategy for developing therapeutic methods in controlling and preventing infectious diseases caused by pathogenic bacteria Pseudomonas aeruginosa, one of which is by using phthalocyanine as a photosensitizer in photodynamic therapy. This study aims to identify, evaluate, and explore the mechanism of action of phthalocyanine compounds against HasAp proteins, and their effects on the active site of HasR through in silico studies. Ligand-protein docking studies were performed using MGLTools 1.5.6 with AutoDock 4.2 to observe the affinity and molecular interactions between molecules of Fe-phthalocyanine (Fe-Pc) and Ga-phthalocyanine (Ga-Pc) against HasAp protein macromolecules. Furthermore, a protein-protein docking study of the ligand-protein complexes system was simulated to observe its effect on the binding area of the HasR protein macromolecules using PatchDock. Based on the ligand-protein docking results, Fe-phthalocyanine (Fe-Pc) compounds have the best affinity for both HasAp proteins, with a binding energy value of -68.45 kJ/mol and -69.16 kJ/mol, respectively. The protein-protein docking study results between the complex compound Fe-phthalocyanine (Fe-Pc) and HasAp protein against HasR protein have a positive Atomic Contact Energy (ACE) value, with an ACE value of 556.56 kJ/mol. Differences in the molecular structure of phthalocyanine compounds are proven to be able to influence the mechanism of action against the target protein. Therefore, the results of this study can be a reference in designing the structure of phthalocyanine compounds as photosensitizer candidates in photodynamic therapy.

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434.v1 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

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Microbiological quality of residues from drinking water preparation

Water Science & Technology ◽

10.2166/wst.1995.0565 ◽

1995 ◽

Vol 31 (5-6) ◽

pp. 75-79 ◽

Cited By ~ 5

Author(s):

M. Würzer ◽

A. Wiedenmann ◽

K. Botzenhart

Keyword(s):

Waste Water ◽

Escherichia Coli ◽

Pseudomonas Aeruginosa ◽

Drinking Water ◽

Water Treatment ◽

Pathogenic Bacteria ◽

Waste Water Treatment ◽

Microbiological Quality ◽

Detection Limits

In Germany the application of procedures such as flocculation and filtration in the preparation of drinking water results in the annual production of an estimated 500,000 t of sediments and sludges. Some of these residues have a potential for being reused, for example in agriculture, forestry, brickworks or waste water treatment. To assess the microbiological quality of residues from waterworks methods for the detection of enterobacteria, Escherichia coli, Salmonella, Pseudomonas aeruginosa, Legionella, poliovirus, Ascaris suis eggs and Cryptosporidium have been evaluated regarding their detection limits and were applied to various residues from German waterworks. Results show that sediments and sludges may contain pathogenic bacteria, viruses and protista. When residues from waterworks are intended to be reused in agriculture or forestry the microbiological quality should therefore be considered.

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The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323999200824115536 ◽

2020 ◽

Vol 23 ◽

Author(s):

Sisir Nandi ◽

Mohit Kumar ◽

Mridula Saxena ◽

Anil Kumar Saxena

Keyword(s):

Molecular Docking ◽

In Silico ◽

Drug Repurposing ◽

Clinical Settings ◽

The Novel ◽

In Silico Docking ◽

Biochemical Mechanisms ◽

Novel Coronavirus ◽

In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

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Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Current Alzheimer Research ◽

10.2174/1567205016666181212155147 ◽

2019 ◽

Vol 16 (2) ◽

pp. 116-127 ◽

Cited By ~ 2

Author(s):

Ashwani Kumar ◽

Vineet Mehta ◽

Utkarsh Raj ◽

Pritish Kumar Varadwaj ◽

Malairaman Udayabanu ◽

...

Keyword(s):

In Silico ◽

Hippocampal Neurons ◽

Symptomatic Relief ◽

In Vitro Assays ◽

Disease Modifying Drugs ◽

In Silico Docking ◽

Ache Inhibitors ◽

Significant Difference ◽

Disease Modifying

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer’s disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

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