Holmboevegen 3B

Tromsø, Norway

Holmboevegen 3B

Tromsø, Norway
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Le-Thi-Thu H.,Vietnam National University, Hanoi | Casanola-Martin G.M.,University of Valencia | Marrero-Ponce Y.,University of Cartagena | Rescigno A.,University of Cagliari | And 2 more authors.
Current Topics in Medicinal Chemistry | Year: 2014

The tyrosinase is a bifunctional, copper-containing enzyme widely distributed in the phylogenetic tree. This enzyme is involved in the production of melanin and some other pigments in humans, animals and plants, including skin pigmentations in mammals, and browning process in plants and vegetables. Therefore, enzyme inhibitors has been under the attention of the scientist community, due to its broad applications in food, cosmetic, agricultural and medicinal fields, to avoid the undesirable effects of abnormal melanin overproduction. However, the research of novel chemical with antityrosinase activity demands the use of more efficient tools to speed up the tyrosinase inhibitors discovery process. This chapter is focused in the different components of a predictive modeling workflow for the identification and prioritization of potential new compounds with activity against the tyrosinase enzyme. In this case, two structure chemical libraries Spectrum Collection and Drugbank are used in this attempt to combine different virtual screening data mining techniques, in a sequential manner helping to avoid the usually expensive and time consuming traditional methods. Some of the sequential steps summarize here comprise the use of drug-likeness filters, similarity searching, classification and potency QSAR multiclassifier systems, modeling molecular interactions systems, and similarity/diversity analysis. Finally, the methodologies showed here provide a rational workflow for virtual screening hit analysis and selection as a promissory drug discovery strategy for use in target identification phase. © 2014 Bentham Science Publishers.


Samshuddin S.,Mangalore University | Narayana B.,Mangalore University | Sarojini B.K.,P.A. College | Khan M.T.H.,Holmboevegen 3B | And 3 more authors.
Medicinal Chemistry Research | Year: 2012

A series of 1,3,5-triaryl-2-pyrazolines 2a-g were synthesized by the reaction of 4,40-disubstituted chalcone with phenyl hydrazine. All these compounds were characterized by NMR, IR and mass spectral and single crystal XRD data. All the synthesized products were screened for their in vitro antimicrobial, analgesic and antioxidant properties. The docking studies were carried out for these compounds against the active site of methionyl-tRNA synthetase (metRS). Some of the tested compounds exhibited significant antimicrobial, analgesic, DPPH scavenging activities and molecular binding. © Springer Science+Business Media, LLC 2011.


Senol F.S.,Gazi University | Khan M.T.H.,Holmboevegen 3B | Orhan G.,Numune Training and Research Hospital | Gurkas E.,Numune Training and Research Hospital | And 3 more authors.
Current Topics in Medicinal Chemistry | Year: 2014

Current evidence suggests that endogenous dopamine may act as a neurotoxin following its oxidation to an oquinone and reaction with cellular thiols, which are neutoxic, which may occur spontaneously or via reaction with tyrosinase or some other enzymes. Tyrosinase (E.C. 1.14.18.1) with two cupper ions coordinated by three histidines is a bifunctional enzyme that catalyses both the hydroxylation of tyrosine to L-DOPA and the consequent oxidation of the resulting catechol-containing species to an o-quinone. Therefore, tyrosinase may play a role in neuromelanin formation in the brain and could be central to dopamine neurotoxicity by contributing to the neurodegeneration associated with Parkinson's disease. In the present study, inhibitory effect of ascorbic acid against tyrosinase has been investigated and it has shown a remarkable inhibitory effect in in vitro assays. Then, the in silico-based experiments established through molecular docking calculations and scoring, docking search algorithm, and data plotting indicated that ascorbic acid is strong inhibitor of tyrosinase by interacting with four amino acid units (histidine 263, serine 282, phenylalanine 264, and valin 283) in the active site of the enzyme. The compound also had two long distant hydrogen bindings with Cu1 and Cu2 with distances of 3.57 and 3.41 Å, respectively, through its O5 atom. © 2014 Bentham Science Publishers.


Senol F.S.,Gazi University | Skalicka Wozniak K.,Medical University of Lublin | Khan M.T.H.,Holmboevegen 3B | Erdogan Orhan I.,Gazi University | And 3 more authors.
Phytochemistry Letters | Year: 2011

Cholinesterase inhibitory and antioxidant activities of the methanol extract, furanocoumarin fraction, and major coumarins (imperatorin, xanthotoxin, and bergapten) of the fruits of Angelica officinalis L. growing in Poland were determined in the current study. Cholinesterase inhibition was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at 12.5, 25, 50, and 100 μg mL-1 using ELISA microplate reader. Antioxidant activity of the samples was tested by in vitro models including radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylendiamine (DMPD) as well as ferrous ion-chelation capacity, ferric-(FRAP) and phosphomolibdenum-reducing antioxidant power (PRAP) assays at 500, 1000, and 2000 μg mL-1. The extract was found to have strong inhibition against BChE (85.65 ± 1.49%) and low inhibition against AChE (27.49 ± 2.01%) at 100 μg mL-1. Four major coumarins; imperatorin, isoimperatorin, xanthotoxin, and bergapten were identified in the extract by HPLC. Imperatorin (83.98 ± 0.99%), xanthotoxin (88.04 ± 0.83%), and bergapten (86.69 ± 2.56%) displayed strong inhibition towards BChE. Molecular docking studies confirmed potent interactions between BChE and the tested furanocoumarins. The samples did not possess radical scavenging activity against DPPH and DMPD, whereas they possessed a moderate level of FRAP and PRAP at the tested concentrations. To the best of our knowledge, the current work constitutes the first study on cholinesterase inhibitory and antioxidant activities of A. officinalis. © 2011 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.


Orhan I.E.,Gazi University | Orhan I.E.,Eastern Mediterranean University | Khan M.T.H.,Holmboevegen 3B
Current Topics in Medicinal Chemistry | Year: 2014

Tyrosinase (EC 1.14.18.1), also known as polyphenols oxidase, is a glycosylated multi-copper monooxygenase enzyme widely distributed in many different organisms. The enzyme is responsible for the pigmentation of skin, eyes and hair in mammals and in fruits and vegetables undesired browning. These issues have encouraged researchers all over the world to seek new, potent and safe inhibitors of the enzyme for use in foods and cosmetics. A large number of compounds from natural products have been reported as moderate to potent inhibitors of tyrosinase. Among them, many flavonoid derivatives have been revealed to be the strong inhibitors of tyrosinase. In this review, we reviewed many examples of tyrosinase inhibitors with flavonoid structure reported between 2008-2013. Our findings underline that flavonoids should continue to be the focus of tyrosinase inhibition studies as the promising compounds. © 2014 Bentham Science Publishers.


Murakawa T.,Toyohashi University of Technology | Matsushita Y.,Toyohashi University of Technology | Suzuki T.,Toyohashi University of Technology | Khan M.T.H.,Holmboevegen 3B | Kurita N.,Toyohashi University of Technology
Journal of Molecular Graphics and Modelling | Year: 2014

Butyrylcholinesterase (BChE) exists mainly at neuromuscular junctions and plays an important role in the hydrolyzing mechanism of neurotransmitter acetylcholine. A variety of compounds have been produced in order to inhibit the function of BChE. We here investigate the specific interactions between BChE and some ligands (Kx) with large binding affinity to BChE, using ligand-docking, classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods. The binding energies between BChE and Kx evaluated by the FMO method have a correlation with the 50% inhibition concentration obtained by the previous experiments. In addition, the FMO calculations highlight that Asp70, Trp82 and Tyr128 residues of BChE contribute significantly to the binding between BChE and Kx. Based on the results, we propose some novel ligands and elucidate that one of the proposed ligands can bind strongly to BChE. The present results are useful for developing potent inhibitors to BChE. © 2014 Elsevier Inc. All rights reserved.


A large number of naturally origin alkaloids are reported to be potential against cholinesterases (e.g., acetylcholinesterase, butyrylcholinestarase, etc.). Some of them are from chemical subclass of steroidal alkaloids. Here in this paper docking calculations and the possible intermolecular and atomic interactions have been studied and presented from some of the natural and semisynthetic steroidal alkaloids. These alkaloids were found to be potent inhibitors against both the acetyl- (AChE) and butyrylcholinestarase (BChE). Some (like Terminaline, Hookerianamide I, Chonemorphine, etc.) of them were interestingly found to be quite selective towards the BChE over AChE. For the docking calculations ICM™ docking module and for the study of the intermolecular interactions the program LigPlot have been used. During the docking studies the compounds showed good correlations with the in vitro activity profiles (IC50 values) and the docking (Edocking) and calculated binding energies (ΔG). When docked into AChE the correlation coefficient (R2) 0.808 and 0.813, respectively and when docked into BChE the R2 values were found to be 0.873 and 0.768, respectively. These correlations revealed remarkable agreements of the docking studies with the activity found from in vitro experiments. Majority and the large part of the compounds exhibited hydrogen bonds as well as hydrophobic interactions at the peripheral anionic subsite (PAS), which is at the entrance of the gorge. A number of compounds exhibited interesting interactions both the PAS and acyl-binding sites. © 2013 Bentham Science Publishers.


Kovarova M.,University of Pardubice | Khan M.T.H.,Holmboevegen 3B | Komers K.,University of Pardubice | Parik P.,University of Pardubice | And 2 more authors.
Current Enzyme Inhibition | Year: 2011

Two series A and B of 12 and 7 new carbamate derivates were tested in vitro as acetylcholinesterase inhibitors. The tests were performed in the batch stirred reactor at 25°C, pH 8, ionic strength 0.11 M and catalytic activity of the enzyme preparation 0.14 U mL -1 of the reaction mixture. The temporal dependences of actual concentrations of acetylcholine, choline and acetic acid were determined by two independent analytical methods, HPLC and pH-stat. For all used inhibitors, the model of competitive irreversible inhibition was valid. The inhibition rate constant k 3 and qualified estimation of the absolute acetylcholinesterase concentration in the reaction mixture were calculated. The partition coefficients K ow between n-octanol and water of all used inhibitors were determined. The k 3 and K ow values were correlated with the Hammett and Hansch substituent constants and with the calculated docking and binding energies of the reaction between the tested inhibitors and acetylcholinesterase. © 2011 Bentham Science Publishers.


PubMed | Toyohashi University of Technology and Holmboevegen 3B
Type: | Journal: Journal of molecular graphics & modelling | Year: 2014

Butyrylcholinesterase (BChE) exists mainly at neuromuscular junctions and plays an important role in the hydrolyzing mechanism of neurotransmitter acetylcholine. A variety of compounds have been produced in order to inhibit the function of BChE. We here investigate the specific interactions between BChE and some ligands (Kx) with large binding affinity to BChE, using ligand-docking, classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods. The binding energies between BChE and Kx evaluated by the FMO method have a correlation with the 50% inhibition concentration obtained by the previous experiments. In addition, the FMO calculations highlight that Asp70, Trp82 and Tyr128 residues of BChE contribute significantly to the binding between BChE and Kx. Based on the results, we propose some novel ligands and elucidate that one of the proposed ligands can bind strongly to BChE. The present results are useful for developing potent inhibitors to BChE.

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