Catherine Koukoulitsa - Academia.edu (original) (raw)

Papers by Catherine Koukoulitsa

Research paper thumbnail of Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

Biophysics of Structure and Mechanism, May 8, 2011

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify... more In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).

Research paper thumbnail of Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Journal of Natural Products, Feb 26, 2010

Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2... more Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1beta,4alpha,6alpha-trihydroxyeudesm-11-en-8alpha-12-olide (9), were isolated from the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones against four Gram-positive and five Gram-negative bacteria and one fungus was evaluated using the microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore, the pharmacokinetic profile of the sesquiterpene lactones was investigated using computational methods.

Research paper thumbnail of Testing the 3D QSAR/ComFA-CoMSIA results of flexible bioactive compounds with molecular docking studies

Drugs of the Future, 2007

Research paper thumbnail of Evaluation of aldose reductase inhibition and docking studies of 6′-nitro and 6′,6″-dinitrorosmarinic acids

European Journal of Medicinal Chemistry, Apr 1, 2010

Aldose reductase (ALR2) of the polyol metabolic pathway is a target enzyme for the treatment of d... more Aldose reductase (ALR2) of the polyol metabolic pathway is a target enzyme for the treatment of diabetic complications. A variety of synthetic and natural compounds have been observed to inhibit aldose reductase. Among them, rosmarinic acid has been shown to be in vitro an aldose reductase inhibitor in a micromolar range. In this study, two nitro derivatives of rosmarinic acid synthesized previously, 6 0nitro and 6 0 ,6 00 -dinitrorosmarinic acids, are proposed as aldose reductase inhibitors. Docking studies of the nitro derivatives have been carried out in the active site of aldose reductase. The theoretical results have shown a higher estimated binding energy of both compounds in comparison to that of rosmarinic acid suggesting a higher ALR2 inhibitory activity. The in vitro biological assays confirmed that these compounds were more potent than the parent rosmarinic acid.

Research paper thumbnail of A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: homology modeling, docking, de novo drug design and molecular dynamics analysis

Molecular Diversity, 2010

When X-ray structure of a ligand-bound receptor is not available, homology models of the protein ... more When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377-7387, 2008). In this present study, a homology modeling study based on the β2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the Electronic supplementary material The online version of this article (alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the β2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.

Research paper thumbnail of Partial interdigitation of lipid bilayers

Int J Quantum Chem, 2010

A methodology has been developed to detect partial interdigitation of lipid bilayers when a bioac... more A methodology has been developed to detect partial interdigitation of lipid bilayers when a bioactive molecule is intercalated between the polar, interface, or hydrophobic segments. This methodology uses the easily accessible differential scanning calorimetry (DSC) technique as a screening one and the increase of DH due to the incorporated drug in lipid bilayers as a diagnostic thermodynamic parameter. The combined use of X-ray diffraction and Raman spectroscopy complement and confirm the provided by DSC information as it is shown in three classes of molecules, namely AT 1 antagonists, vinca alkaloids, and anesthetic steroids. For the two classes of molecules, AT 1 antagonists and vinca alkaloids, their presence in lipid bilayers results in the increase of DH and it is accompanied by the increase of trans:gauche ratio and the decrease of d-spacing as depicted by Raman spectroscopy and small-angle X-ray diffraction correspondingly, confirming the predictive ability of DSC experiments. When an anesthetic steroid is incorporated in lipid bilayers, neither increase of DH nor decrease of d-spacing was observed, confirming again the DSC results that show the absence of partial interdigitation of this class of molecules. Molecular dynamics simulations have been carried out for a representative system [(5S)-1benzylo-5-(1H-benzimidazol-1-ylo-methylo)-2-pyrrolidinone (MMK3) ligands at 1,2dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer], and the results confirmed the experimental findings. The change of distance at z-axis of oxygen atoms at head group of lipid molecule has been measured throughout the simulations. Statistical analysis has shown $8.8 Å interdigitation. Derived computational results are encouraging and can be performed to another ligand/lipid system. The development of a theoretical methodology will lead to advance the field and save a valuable time and effort.

Research paper thumbnail of A novel sesquiterpene lactone from Centaurea pullata : Structure elucidation, antimicrobial activity, and prediction of pharmacokinetic properties

Bioorganic Medicinal Chemistry, Apr 1, 2008

A novel elemanolide with an a-methyl-c-lactone moiety, 8a-O-(4-hydroxy-2-methylenebutanoyloxy)mel... more A novel elemanolide with an a-methyl-c-lactone moiety, 8a-O-(4-hydroxy-2-methylenebutanoyloxy)melitensine, in addition to four known sesquiterpene lactones also bearing the same lactone ring, melitensin, 11b,13 dihydrosalonitenolide, 8a-hydroxy-11b,13-dihydro-4-epi-sonchucarpolide, and 8a-hydroxy-11b,13-dihydro-onopordaldehyde have been isolated from the aerial parts of Centaurea pullata. The in vitro antibacterial and antifungal activities of the isolated sesquiterpene lactones were tested against six bacteria and eight fungal species, using a microdilution method. All compounds tested showed greater antibacterial and antifungal activities than the positive controls used. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods.

Research paper thumbnail of Inhibitory effect on soybean lipoxygenase and docking studies of some secondary metabolites, isolated from Origanum vulgare L. ssp. hirtum

In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12... more In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12-hydroxyjasmonic acid 12-O-beta-glucoside and p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside) isolated from the polar extracts of the plant Origanum vulgare L. ssp. hirtum, were tested in vitro for their ability to inhibit soybean lipoxygenase. Among the examined compounds, lithospermic acid B demonstrated the best inhibitory activity on soybean lipoxygenase with IC50 = 0.1 mM. Docking studies have been undertaken as an attempt for better understanding the interactions of these compounds within the active site of soybean lipoxygenase. The predicted binding energy values correlated well with the observed biological data.

Research paper thumbnail of The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-α

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics

In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL),... more In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-alpha (ERalpha) was investigated. ESBL was found to be positioned inside the binding cavity with its steroidal moiety, whereas the alkylating moiety protruded out of receptor's pocket.

Research paper thumbnail of Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, s... more Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl-and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzymeesubstrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide eNHe moiety of compounds and eOH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChEecompound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.

Research paper thumbnail of The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-alpha

Oncology research, 2005

In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL),... more In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-alpha (ERalpha) was investigate...

Research paper thumbnail of A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: Homology modeling, docking, de novo drug design and molecular dynamics analysis

Molecular Diversity, 2010

When X-ray structure of a ligand-bound receptor is not available, homology models of the protein ... more When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377-7387, 2008). In this present study, a homology modeling study based on the β2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the Electronic supplementary material The online version of this article (alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the β2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.

Research paper thumbnail of A simulation study of the interaction of sulfhydryl nucleophiles with several antifungal sesquiterpene lactones isolated from Greek Centaurea sp

Journal of Molecular Structure: THEOCHEM, 2006

Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) poss... more Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial and antifungal. It is well known that the activity of a given sesquiterpene lactone may be determined by the availability and accessibility of vitally important thiol compounds present in specific fungi, such as cysteine and glutathione. A simulation study of the interaction of the sulfhydryl nucleophiles with two germacranolides, selected from a series of natural antifungal sesquiterpene lactones and corresponding semi-synthetic derivatives, was performed through molecular modeling techniques. The Hartree-Fock ab initio calculations revealed that structural modification of the examined natural sesquiterpene lactones may increase their biologic activity. q

Research paper thumbnail of Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

European Journal of Medicinal Chemistry, 2014

Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, s... more Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl-and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzymeesubstrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide eNHe moiety of compounds and eOH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChEecompound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.

Research paper thumbnail of Inhibitory effect of polar oregano extracts on aldose reductase and soybean lipoxygenasein vitro

Phytotherapy Research, 2006

The effect of methanol and aqueous methanol extract of Origanum vulgare L. ssp. hirtum on aldose ... more The effect of methanol and aqueous methanol extract of Origanum vulgare L. ssp. hirtum on aldose reductase and soybean lipoxygenase was investigated. The results revealed a promising potential of oregano for preventing diabetes complications in the long term and an antiinflammatory efficacy by inhibiting soybean lipoxygenase.

Research paper thumbnail of Facile and Efficient Syntheses of a Series of N-Benzyl and N-Biphenylmethyl Substituted Imidazole Derivatives Based on (E)-Urocanic acid, as Angiotensin II AT1 Receptor Blockers

Molecules, 2013

In the present work, a facile and efficient route for the synthesis of a series of N-substituted ... more In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.

Research paper thumbnail of PLS Analysis for Antibacterial Activity of Natural Coumarins Using VolSurf Descriptors

QSAR & Combinatorial Science, 2009

Research paper thumbnail of Correction to Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Journal of Natural Products, 2012

Research paper thumbnail of Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Journal of Natural Products, 2010

Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2... more Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1beta,4alpha,6alpha-trihydroxyeudesm-11-en-8alpha-12-olide (9), were isolated from the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones against four Gram-positive and five Gram-negative bacteria and one fungus was evaluated using the microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore, the pharmacokinetic profile of the sesquiterpene lactones was investigated using computational methods.

Research paper thumbnail of Inhibitory effect on soybean lipoxygenase and docking studies of some secondary metabolites, isolated from Origanum vulgare L. ssp. hirtum

Journal of Enzyme Inhibition and Medicinal Chemistry, 2007

In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12... more In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12-hydroxyjasmonic acid 12-O-beta-glucoside and p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside) isolated from the polar extracts of the plant Origanum vulgare L. ssp. hirtum, were tested in vitro for their ability to inhibit soybean lipoxygenase. Among the examined compounds, lithospermic acid B demonstrated the best inhibitory activity on soybean lipoxygenase with IC50 = 0.1 mM. Docking studies have been undertaken as an attempt for better understanding the interactions of these compounds within the active site of soybean lipoxygenase. The predicted binding energy values correlated well with the observed biological data.

Research paper thumbnail of Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

Biophysics of Structure and Mechanism, May 8, 2011

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify... more In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).

Research paper thumbnail of Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Journal of Natural Products, Feb 26, 2010

Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2... more Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1beta,4alpha,6alpha-trihydroxyeudesm-11-en-8alpha-12-olide (9), were isolated from the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones against four Gram-positive and five Gram-negative bacteria and one fungus was evaluated using the microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore, the pharmacokinetic profile of the sesquiterpene lactones was investigated using computational methods.

Research paper thumbnail of Testing the 3D QSAR/ComFA-CoMSIA results of flexible bioactive compounds with molecular docking studies

Drugs of the Future, 2007

Research paper thumbnail of Evaluation of aldose reductase inhibition and docking studies of 6′-nitro and 6′,6″-dinitrorosmarinic acids

European Journal of Medicinal Chemistry, Apr 1, 2010

Aldose reductase (ALR2) of the polyol metabolic pathway is a target enzyme for the treatment of d... more Aldose reductase (ALR2) of the polyol metabolic pathway is a target enzyme for the treatment of diabetic complications. A variety of synthetic and natural compounds have been observed to inhibit aldose reductase. Among them, rosmarinic acid has been shown to be in vitro an aldose reductase inhibitor in a micromolar range. In this study, two nitro derivatives of rosmarinic acid synthesized previously, 6 0nitro and 6 0 ,6 00 -dinitrorosmarinic acids, are proposed as aldose reductase inhibitors. Docking studies of the nitro derivatives have been carried out in the active site of aldose reductase. The theoretical results have shown a higher estimated binding energy of both compounds in comparison to that of rosmarinic acid suggesting a higher ALR2 inhibitory activity. The in vitro biological assays confirmed that these compounds were more potent than the parent rosmarinic acid.

Research paper thumbnail of A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: homology modeling, docking, de novo drug design and molecular dynamics analysis

Molecular Diversity, 2010

When X-ray structure of a ligand-bound receptor is not available, homology models of the protein ... more When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377-7387, 2008). In this present study, a homology modeling study based on the β2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the Electronic supplementary material The online version of this article (alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the β2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.

Research paper thumbnail of Partial interdigitation of lipid bilayers

Int J Quantum Chem, 2010

A methodology has been developed to detect partial interdigitation of lipid bilayers when a bioac... more A methodology has been developed to detect partial interdigitation of lipid bilayers when a bioactive molecule is intercalated between the polar, interface, or hydrophobic segments. This methodology uses the easily accessible differential scanning calorimetry (DSC) technique as a screening one and the increase of DH due to the incorporated drug in lipid bilayers as a diagnostic thermodynamic parameter. The combined use of X-ray diffraction and Raman spectroscopy complement and confirm the provided by DSC information as it is shown in three classes of molecules, namely AT 1 antagonists, vinca alkaloids, and anesthetic steroids. For the two classes of molecules, AT 1 antagonists and vinca alkaloids, their presence in lipid bilayers results in the increase of DH and it is accompanied by the increase of trans:gauche ratio and the decrease of d-spacing as depicted by Raman spectroscopy and small-angle X-ray diffraction correspondingly, confirming the predictive ability of DSC experiments. When an anesthetic steroid is incorporated in lipid bilayers, neither increase of DH nor decrease of d-spacing was observed, confirming again the DSC results that show the absence of partial interdigitation of this class of molecules. Molecular dynamics simulations have been carried out for a representative system [(5S)-1benzylo-5-(1H-benzimidazol-1-ylo-methylo)-2-pyrrolidinone (MMK3) ligands at 1,2dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer], and the results confirmed the experimental findings. The change of distance at z-axis of oxygen atoms at head group of lipid molecule has been measured throughout the simulations. Statistical analysis has shown $8.8 Å interdigitation. Derived computational results are encouraging and can be performed to another ligand/lipid system. The development of a theoretical methodology will lead to advance the field and save a valuable time and effort.

Research paper thumbnail of A novel sesquiterpene lactone from Centaurea pullata : Structure elucidation, antimicrobial activity, and prediction of pharmacokinetic properties

Bioorganic Medicinal Chemistry, Apr 1, 2008

A novel elemanolide with an a-methyl-c-lactone moiety, 8a-O-(4-hydroxy-2-methylenebutanoyloxy)mel... more A novel elemanolide with an a-methyl-c-lactone moiety, 8a-O-(4-hydroxy-2-methylenebutanoyloxy)melitensine, in addition to four known sesquiterpene lactones also bearing the same lactone ring, melitensin, 11b,13 dihydrosalonitenolide, 8a-hydroxy-11b,13-dihydro-4-epi-sonchucarpolide, and 8a-hydroxy-11b,13-dihydro-onopordaldehyde have been isolated from the aerial parts of Centaurea pullata. The in vitro antibacterial and antifungal activities of the isolated sesquiterpene lactones were tested against six bacteria and eight fungal species, using a microdilution method. All compounds tested showed greater antibacterial and antifungal activities than the positive controls used. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods.

Research paper thumbnail of Inhibitory effect on soybean lipoxygenase and docking studies of some secondary metabolites, isolated from Origanum vulgare L. ssp. hirtum

In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12... more In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12-hydroxyjasmonic acid 12-O-beta-glucoside and p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside) isolated from the polar extracts of the plant Origanum vulgare L. ssp. hirtum, were tested in vitro for their ability to inhibit soybean lipoxygenase. Among the examined compounds, lithospermic acid B demonstrated the best inhibitory activity on soybean lipoxygenase with IC50 = 0.1 mM. Docking studies have been undertaken as an attempt for better understanding the interactions of these compounds within the active site of soybean lipoxygenase. The predicted binding energy values correlated well with the observed biological data.

Research paper thumbnail of The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-α

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics

In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL),... more In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-alpha (ERalpha) was investigated. ESBL was found to be positioned inside the binding cavity with its steroidal moiety, whereas the alkylating moiety protruded out of receptor's pocket.

Research paper thumbnail of Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, s... more Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl-and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzymeesubstrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide eNHe moiety of compounds and eOH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChEecompound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.

Research paper thumbnail of The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-alpha

Oncology research, 2005

In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL),... more In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-alpha (ERalpha) was investigate...

Research paper thumbnail of A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: Homology modeling, docking, de novo drug design and molecular dynamics analysis

Molecular Diversity, 2010

When X-ray structure of a ligand-bound receptor is not available, homology models of the protein ... more When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377-7387, 2008). In this present study, a homology modeling study based on the β2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the Electronic supplementary material The online version of this article (alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the β2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.

Research paper thumbnail of A simulation study of the interaction of sulfhydryl nucleophiles with several antifungal sesquiterpene lactones isolated from Greek Centaurea sp

Journal of Molecular Structure: THEOCHEM, 2006

Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) poss... more Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial and antifungal. It is well known that the activity of a given sesquiterpene lactone may be determined by the availability and accessibility of vitally important thiol compounds present in specific fungi, such as cysteine and glutathione. A simulation study of the interaction of the sulfhydryl nucleophiles with two germacranolides, selected from a series of natural antifungal sesquiterpene lactones and corresponding semi-synthetic derivatives, was performed through molecular modeling techniques. The Hartree-Fock ab initio calculations revealed that structural modification of the examined natural sesquiterpene lactones may increase their biologic activity. q

Research paper thumbnail of Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

European Journal of Medicinal Chemistry, 2014

Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, s... more Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl-and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzymeesubstrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide eNHe moiety of compounds and eOH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChEecompound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.

Research paper thumbnail of Inhibitory effect of polar oregano extracts on aldose reductase and soybean lipoxygenasein vitro

Phytotherapy Research, 2006

The effect of methanol and aqueous methanol extract of Origanum vulgare L. ssp. hirtum on aldose ... more The effect of methanol and aqueous methanol extract of Origanum vulgare L. ssp. hirtum on aldose reductase and soybean lipoxygenase was investigated. The results revealed a promising potential of oregano for preventing diabetes complications in the long term and an antiinflammatory efficacy by inhibiting soybean lipoxygenase.

Research paper thumbnail of Facile and Efficient Syntheses of a Series of N-Benzyl and N-Biphenylmethyl Substituted Imidazole Derivatives Based on (E)-Urocanic acid, as Angiotensin II AT1 Receptor Blockers

Molecules, 2013

In the present work, a facile and efficient route for the synthesis of a series of N-substituted ... more In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.

Research paper thumbnail of PLS Analysis for Antibacterial Activity of Natural Coumarins Using VolSurf Descriptors

QSAR & Combinatorial Science, 2009

Research paper thumbnail of Correction to Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Journal of Natural Products, 2012

Research paper thumbnail of Sesquiterpene Lactones from Anthemis melanolepis and Their Antibacterial and Cytotoxic Activities. Prediction of Their Pharmacokinetic Profile

Journal of Natural Products, 2010

Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2... more Nine sesquiterpene lactones, anthemin A (1), 1alpha-hydroxydeacetylirinol-4alpha,5beta-epoxide (2), anthemin C (3), tatridin A (4), 1-epi-tatridin B (5), anthemin B (6), 6-deacetyl-beta-cyclopyrethrosin (7), elegalactone A (8), and 1beta,4alpha,6alpha-trihydroxyeudesm-11-en-8alpha-12-olide (9), were isolated from the aerial parts of A. melanolepis in addition to eight known flavonoids and three phenolic acids. Compounds 1, 3, and 6 are new natural products. The structures of the compounds were deduced by spectroscopic methods. The in vitro antimicrobial potential of the isolated sesquiterpene lactones against four Gram-positive and five Gram-negative bacteria and one fungus was evaluated using the microdilution method, and their in vitro cytotoxic activity was determined against a panel of human tumor cell lines. Furthermore, the pharmacokinetic profile of the sesquiterpene lactones was investigated using computational methods.

Research paper thumbnail of Inhibitory effect on soybean lipoxygenase and docking studies of some secondary metabolites, isolated from Origanum vulgare L. ssp. hirtum

Journal of Enzyme Inhibition and Medicinal Chemistry, 2007

In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12... more In this study, five secondary metabolites (caffeic acid, rosmarinic acid, lithospermic acid B, 12-hydroxyjasmonic acid 12-O-beta-glucoside and p-menth-3-ene-1,2-diol 1-O-beta-glucopyranoside) isolated from the polar extracts of the plant Origanum vulgare L. ssp. hirtum, were tested in vitro for their ability to inhibit soybean lipoxygenase. Among the examined compounds, lithospermic acid B demonstrated the best inhibitory activity on soybean lipoxygenase with IC50 = 0.1 mM. Docking studies have been undertaken as an attempt for better understanding the interactions of these compounds within the active site of soybean lipoxygenase. The predicted binding energy values correlated well with the observed biological data.