Discovery of new butyrylcholinesterase inhibitors via structure-based virtual screening

Atatreh, Noor; Rawashdah, Sara Al; Neyadi, Shaikha S. Al; Abuhamdah, Sawsan; Ghattas, Mohammad A.

doi:10.1080/14756366.2019.1644329

Cited by 35 publications

(22 citation statements)

References 42 publications

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“…To date, scientists have failed to find a cure for AD due to the lack of understanding on the causes and mechanisms of the disease [ 9 ]. As a therapeutic strategy, cholinesterase inhibitors as donepezil, rivastigmine and galantamine are prescribed to patients to help postponing the symptoms of AD, but they present significant side effects [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Chromatographic Separation of Breynia retusa (Dennst.) Alston Bark, Fruit and Leaf Constituents from Bioactive Extracts

et al. 2020

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Breynia retusa (Dennst.) Alston (also known as Cup Saucer plant) is a food plant with wide applications in traditional medicine, particularly in Ayurveda. Extracts obtained with four solvents (dichloromethane, methanol, ethyl acetate and water), from three plant parts, (fruit, leaf and bark) were obtained. Extracts were tested for total phenolic, flavonoid content and antioxidant activities using a battery of assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC), total antioxidant capacity (TAC) (phosphomolybdenum) and metal chelating. Enzyme inhibitory effects were investigated using acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, α-amylase and α-glucosidase as target enzymes. Results showed that the methanolic bark extract exhibited significant radical scavenging activity (DPPH: 202.09 ± 0.15; ABTS: 490.12 ± 0.18 mg Trolox equivalent (TE)/g), reducing potential (FRAP: 325.86 ± 4.36: CUPRAC: 661.82 ± 0.40 mg TE/g) and possessed the highest TAC (3.33 ± 0.13 mmol TE/g). The methanolic extracts were subjected to LC-DAD-MSn and NMR analysis. A two-column LC method was developed to separate constituents, allowing to identify and quantify forty-four and fifteen constituents in bark and fruits, respectively. Main compound in bark was epicatechin-3-O-sulphate and isolation of compound was performed to confirm its identity. Bark extract contained catechins, procyanidins, gallic acid derivatives and the sulfur containing spiroketal named breynins. Aerial parts mostly contained flavonoid glycosides. Considering the bioassays, the methanolic bark extract resulted a potent tyrosinase (152.79 ± 0.27 mg kojic acid equivalent/g), α-amylase (0.99 ± 0.01 mmol acarbose equivalent ACAE/g) and α-glucosidase (2.16 ± 0.01 mmol ACAE/g) inhibitor. In conclusion, methanol is able to extract the efficiently the phytoconstituents of B. retusa and the bark is the most valuable source of compounds.

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Section: Introductionmentioning

confidence: 99%

Chromatographic Separation of Breynia retusa (Dennst.) Alston Bark, Fruit and Leaf Constituents from Bioactive Extracts

et al. 2020

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“…If drug candidates are Cytochrome P450 enzyme substrates they would be administered with inhibitors to facilitate their metabolism[54]. FromTable 2, all lead compounds are neither inhibitors nor substrates of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 enzymes.The predicted excretion values for Total Clearance for the standard, and the lead compounds are within pharmacological range[23]. Similarly, they all are predicted to be non-substrates of Renal Organic Cation Transporter 2 (OCT2).…”

mentioning

confidence: 79%

“…Ligand preparation: A library of 1,048 compounds obtained from edible African plants such as fruits, spices, and vegetables were downloaded from PubChem database [22]. All the compounds had been prescreened for Lipinski (hydrogen bond donor (HBD) ≤ 5, hydrogen bond acceptor (HBA) ≤ 10, molecular weight ≤ 500, and logP ≤ 5) and Veber (polar surface area (PSA) ≤ 140, and rotatable bonds ≤ 10) rules [23]. The 3D structures of all the compounds, and that of the standard, Sinefungin (PubChem CID 65482) were downloaded from PubChem in the structure-data file (sdf) format [22].…”

Section: Methodsmentioning

confidence: 99%

In Silico Identification of the Potential Natural Inhibitors of SARS-CoV-2 Guanine-N7 Methyltransferase.

Rowaiye¹,

Onuh²,

Oladimeji-Salami³

et al. 2020

Preprint

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The outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 has triggered intense scientific research into the possible therapeutic strategies that can combat the ravaging disease. One of such strategies is the inhibition of an important enzyme that affects an important physiological process of the virus. The enzyme, Guanine 7 Methyltransferase is responsible for the capping of the SARS-CoV-2 mRNA to conceal it from the host’s cellular defense. The study aims at computationally identifying the potential natural inhibitors of the SARS-CoV-2 GuanineN7 methyltransferase binding at the active site (Pocket 41). A library of small molecules was obtained from edible African plants and were molecularly docked against the SARS-CoV-2 Guanine-N7 methyltransferase (QHD43415_13. pdb) using the Pyrx software. Sinefungin, an approved antiviral drug which had a binding score of -7.6 kcal/ mol with the target was chosen as a standard. Using the molecular descriptors of the compounds, a virtual screening for oral availability was performed using the Pubchem and SWISSADME web tools. The online servers PKCSM and Molinspiration were used for further screening for pharmacokinetic properties and bioactivity respectively. The molecular dynamic simulation and analyses of the Apo and Holo proteins was performed using the GROMACS software on the Galaxy webserver. The lead compounds are Crinamidine, Marmesin and Sinensetin which are obtained from waterleaf, mango, and orange plants respectively. All the lead compounds performed better than the standard. Crinamidine is predicted to show the greatest inhibitory activity. Further tests are required to further investigate the inhibitory activities of the lead compounds.

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“…molecular weight ≤ 500, hydrogen bond donor (HBD) ≤ 5, hydrogen bond acceptor (HBA) ≤ 10, logP ≤ 5, polar surface area (PSA) ≤ 140, and rotatable bonds ≤ 10. 29 Their 3D structures and that of the reference compound, Triphenylmethane (PubChem CID 10614) were downloaded from PubChem in sdf format. 28…”

Section: Methodsmentioning

confidence: 99%

In Silico Identification of Potential Allosteric Inhibitors of the SARS-CoV-2 Helicase

2021

TJNPR

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The Coronavirus disease 2019 (COVID-19) pandemic currently affects 213 countries and territories around the world. As of April 15, 2020, the World Health Organization (WHO) has reported about 2,000,000 global cases of COVID-19 with 128,886 deaths. 1 COVID-19 is an infectious disease caused by a 2019-novel coronavirus (SARS-CoV-2) which spreads through the buccal and nasal discharges from infected persons. The disease can be asymptomatic but also present a range of symptoms such as fever, dry cough, fatigue, body pains, sore throat, diarrhea, headache, and loss of smell or taste. In severe cases, patients suffer pneumonia, severe acute respiratory syndrome, multi-organ failure, and death. 2 The WHO is yet to approve any vaccine or antiviral drug for the prevention or treatment of coronavirus infections. However, CoV-associated pathologies have been treated with some existing broad-spectrum antiviral drugs. Most treatment strategies focus on the management of symptoms and supportive therapy. 3,4 Coronaviruses (CoVs) have been known to infect a wide variety of mammals and birds causing respiratory and enteric diseases. They are classified into four different genera namely the alpha-, beta-, gamma-, and delta-CoVs. The CoV genome is susceptible to frequent mutations and recombination which can give rise to new strains of varying virulence. 5 There are seven strains of human CoVs and their major

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Discovery of new butyrylcholinesterase inhibitors via structure-based virtual screening

Cited by 35 publications

References 42 publications

Chromatographic Separation of Breynia retusa (Dennst.) Alston Bark, Fruit and Leaf Constituents from Bioactive Extracts

Chromatographic Separation of Breynia retusa (Dennst.) Alston Bark, Fruit and Leaf Constituents from Bioactive Extracts

In Silico Identification of the Potential Natural Inhibitors of SARS-CoV-2 Guanine-N7 Methyltransferase.

In Silico Identification of Potential Allosteric Inhibitors of the SARS-CoV-2 Helicase

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