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Publication Metadata only Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives(Elsevier Ltd, 2017) Zengin Kurt, Belma; Gazioğlu, Işil; Daǧ, Aydan; Salmas, Ramin Ekhteiari; Kayık, Gülru; Durdagi, Serdar; Sönmez, Fatih; Zengin Kurt, Belma, Department of Pharmaceutical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Gazioğlu, Işil, Department of Analytical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Daǧ, Aydan, Department of Pharmaceutical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kayık, Gülru, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Sönmez, Fatih, Pamukova Vocational High School, Sakarya Üniversitesi, Serdivan, TurkeyNew thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50values of 2.22 μM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50value of 0.02 μM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07–10 μM. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post-processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) approaches). © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Atomistic molecular dynamics simulations of typical and atypical antipsychotic drugs at the dopamine D2 receptor (D2R) elucidates their inhibition mechanism(Taylor and Francis Ltd. [email protected], 2017) Salmas, Ramin Ekhteiari; Yurtsever, Mine; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyDopamine D2 receptor (D2R) plays a pivotal role in nervous systems. Its dysfunction leads to the schizophrenia, Parkinson’s diseases and drug addiction. Since the crystal structure of the D2R was not solved yet, discovering of potent and highly selective anti-psychotic drugs carry challenges for different neurodegenerative diseases. In the current study, we modeled the three-dimensional (3D) structure of the D2R based on a recently crystallized structure of the dopamine D3 receptor. These two receptors share a high amino acid sequence homology (>70%). The interaction of the modeled receptor with well-known atypical and typical anti-psychotic drugs and the inhibition mechanisms of drugs at the catalytic domain were studied via atomistic molecular dynamics simulations. Our results revealed that, class-I and class-II forms of atypical and typical D2R antagonists follow different pathways in the inhibition of the D2Rs. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor(American Chemical Society [email protected], 2017) Salmas, Ramin Ekhteiari; Seeman, Philip; Aksoydan, Busecan; Stein, Matthias Jeanette; Yurtsever, Mine; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Seeman, Philip, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Stein, Matthias Jeanette, Molecular Simulations and Design Group, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [3H](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO) revealed Ki values of 32 nM for the D2highR and 52 μM for the D2lowR. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2highR were -9.46 and -8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2highR is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2highR conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Identification of novel serotonin reuptake inhibitors targeting central and allosteric binding sites: A virtual screening and molecular dynamics simulations study(Elsevier Inc. [email protected], 2017) Erol, Ismail; Aksoydan, Busecan; Kantarcioglu, Isik; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kantarcioglu, Isik, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe serotonin (5-hydroxytryptamine, 5HT) transporter (SERT) is a member of neurotransmitter sodium symporter (NSS) family, which maintains neurotransmitter by reuptaking 5HT into synapses. Decrease in serotonin concentrations in synaptic clefts have been reported to cause psychological and neurological disorders. Therefore, inhibition of SERT is a potent strategy for the treatment of related diseases such as depression. In this study, approximately 260,000 small molecules from an available chemical database have been virtually screened both at central and allosteric binding sites of SERT to identify potent novel candidate SERT inhibitors. A set of docking algorithms were used to predict binding modes and energies of compounds. Screening analyses led three top-ranked hit compounds (160234, Otava ID: 7118020138, 159166, Otava ID: 7117171303, and 69419, Otava ID: 118671819) for central binding site (S1) and one compound (93507, Otava ID: 6248262) for allosteric binding site (S2). These promising compounds are then subjected to long multiple molecular dynamics (MD) simulations to elucidate their structural and dynamical profiles at the binding cavities of SERT. Higher predicted binding affinities of identified compounds were also confirmed with binding free energy calculations (MM/GBSA) in comparison with the reference central and allosteric binding site inhibitors, paroxetine (8PR) and escitalopram (68P), respectively. To the best of our knowledge, the present work is the first structure-based high throughput virtual screening study reported using recently revealed crystal structure of SERT for screening inhibitors from chemical databases on S1 and S2 binding sites. Small molecule library screening study yielded candidate compounds both at central and allosteric binding site of SERT, and further experimentation may pave the way for developing novel strong inhibitors. © 2018 Elsevier B.V., All rights reserved.Publication Metadata only First universal pharmacophore model for hERG1 K+ channel activators: acthER(Elsevier Inc. [email protected], 2017) Durdagi, Serdar; Erol, Ismail; Salmas, Ramin Ekhteiari; Patterson, Matthew; Noskov, Sergei Yu; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Patterson, Matthew, Department of Biological Sciences, University of Calgary, Calgary, Canada; Noskov, Sergei Yu, Department of Biological Sciences, University of Calgary, Calgary, CanadaThe intra-cavitary drug blockade of hERG1 channel has been extensively studied, both experimentally and theoretically. Structurally diverse ligands inadvertently block the hERG1 K+ channel currents lead to drug induced Long QT Syndrome (LQTS). Accordingly, designing either hERG1 channel openers or current activators, with the potential to target other binding pockets of the channel, has been introduced as a viable approach in modern anti-arrhythmia drug development. However, reports and investigations on the molecular mechanisms underlying activators binding to the hERG1 channel remain sparse and the overall molecular design principles are largely unknown. Most of the hERG1 activators were discovered during mandatory screening for hERG1 blockade. To fill this apparent deficit, the first universal pharmacophore model for hERG1 K+ channel activators was developed using PHASE. 3D structures of 18 hERG1 K+ channel activators and their corresponding measured binding affinity values were used in the development of pharmacophore models. These compounds spanned a range of structurally different chemotypes with moderate variation in binding affinity. A five sites AAHRR (A, hydrogen-bond accepting, H, hydrophobic, R, aromatic) pharmacophore model has shown reasonable high statistical results compared to the other developed more than 1000 hypotheses. This model was used to construct steric and electrostatic contour maps. The predictive power of the model was tested with 3 external test set compounds as true unknowns. Finally, the pharmacophore model was combined with the previously developed receptor-based model of hERG1 K+ channel to develop and screen novel activators. The results are quite striking and it suggests a greater future role for pharmacophore modeling and virtual drug screening simulations in deciphering complex patterns of molecular mechanisms of hERG1 channel openers at the target sites. The developed model is available upon request and it may serve as basis for the synthesis of novel therapeutic hERG1 activators. © 2018 Elsevier B.V., All rights reserved.Publication Metadata only Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies(Taylor and Francis Ltd. [email protected], 2017) Salmas, Ramin Ekhteiari; Ünlü, Ayhan; Bektaş, Muhammet; Yurtsever, Mine; Mestanoglu, Mert; Durdagi, Serdar; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ünlü, Ayhan, Department of Biophysics, Trakya Üniversitesi, Edirne, Turkey; Bektaş, Muhammet, Department of Biophysics, İstanbul Tıp Fakültesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Mestanoglu, Mert, School of Medicine, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyPoly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study, we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. A total of 257,951 ligands from Otava database were screened at the binding pocket of PARP-1 using high-throughput virtual screening techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e. Glide/standard precision, Glide/XP, induced fit docking–IFD, and quantum mechanics polarized ligand docking–QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 and 63 μM against PARP-1 target, respectively. The molecular mechanism analysis, free energy perturbation calculations using long multiple molecular dynamics simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only The synthesis of novel sulfamides derived from β-benzylphenethylamines as acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase enzymes inhibitors(Academic Press Inc. [email protected], 2017) Akıncıoğlu, Akın; Kocaman, Ebutalib Talip; Akıncıoğlu, Hulya; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Gülçın, İlhami; Supuran, Claudiu T.; Göksu, Süleyman; Akıncıoğlu, Akın, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey, Central Research and Application Laboratory, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Kocaman, Ebutalib Talip, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Akıncıoğlu, Hulya, Central Research and Application Laboratory, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Gülçın, İlhami, Department of Chemistry, Atatürk Üniversitesi, Erzurum, Turkey; Supuran, Claudiu T., Dipartimento di Chimica Ugo Schiff, Università degli Studi di Firenze, Florence, Italy, NEUROFARBA Department, Università degli Studi di Firenze, Florence, Italy; Göksu, Süleyman, Department of Chemistry, Atatürk Üniversitesi, Erzurum, TurkeyIn this study, a series of novel β-benzylphenethylamines and their sulfamide derivatives were synthesized starting from (Z)-2,3-diphenylacrylonitriles. Pd-C catalysed hydrogenation of diphenylacrylonitriles, reduction of propanenitriles with LiAlH4 in the presence of AlCl3 followed by addition of conc. HCl afforded β-benzylphenethylamine hydrochloride salts. The reactions of these amine hydrochloride salts with chlorosulfonyl isocyanate (CSI) in the presence of tert-BuOH and excess Et3N gave sulfamoylcarbamates. Removing of Boc group from the synthesized sulfamoylcarbamates with trifluoroacetic acid (TFA) yielded novel sulfamides in good yields. These novel sulfamides derived from β-benzylphenethylamines were effective inhibitors of the cytosolic carbonic anhydrase I and II isoenzymes (hCA I and II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with Ki values in the range of 0.278–2.260 nM for hCA I, 0.187–1.478 nM for hCA II, 0.127–2.452 nM for AChE and 0.494–1.790 nM for BChE. The inhibitory effects of the synthesized novel sulfamides derived from β-benzylphenethylamines were compared to those of acetazolamide and dorzolamide as clinical hCA I and II isoenzymes inhibitors and tacrine as a clinical AChE and BChE enzymes inhibitors. In addition to in vitro tests, molecular modeling approaches are implemented not only for prediction of the binding affinities of the compounds but also to study their inhibition mechanisms in atomic level at the catalytic domains. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies(Elsevier Inc. [email protected], 2018) Mirza, Shaher Bano; Lee, Regina Ching Hua; Chu, Justin Jang Hann; Salmas, Ramin Ekhteiari; Mavromoustakos, Thomas M.; Durdagi, Serdar; Mirza, Shaher Bano, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, United States, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan; Lee, Regina Ching Hua, Department of Microbiology and Immunology, NUS Yong Loo Lin School of Medicine, Singapore City, Singapore; Chu, Justin Jang Hann, Department of Microbiology and Immunology, NUS Yong Loo Lin School of Medicine, Singapore City, Singapore; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Mavromoustakos, Thomas M., Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyDengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of Dengue virus. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group. In this study, in order to investigate the effect of extended time of molecular dynamics (MD) simulations on structural and dynamical profiles of used complexes, simulation run time is increased from 50-ns to 100-ns for the each system. In addition, a well-known Dengue virus inhibitor (MB21) from literature is used as reference structure (positive control) to compare the proposed molecules. Post-processing MD analyses including Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations were conducted to predict binding free energies of inhibitors from derived trajectory frames of MD simulations. Identified compounds are further directed to Quantum-Polarized Ligand Docking (QPLD), molecular fingerprint-based virtual screening of another small molecule database (Otava Drug Like small molecule database), and Structure-based Pharmacophore Modeling (E-Pharmacophore). Finally, cell proliferation and cytotoxicity tests as well as pre- and post-treatment on HUH7 cells infected with DENV2 NGC strain are applied for four identified hit molecules (ZINC36681949, ZINC44921800, ZINC95518765 and ZINC39500661) to check whether these drugs inhibit DENV2 from entry and/or exit pathways. Based on cell-based Dengue quantification assays, there is no effect seen on pre-treatment of cells with these compounds indicating that the early infection processes of virus is not affected. In contrast, the post-treatment of cells with these compounds after Dengue virus infection has resulted in a significant 1 log PFU/ml reduction of the virus infectious titre. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only Structure-based design of hERG-neutral antihypertensive oxazalone and imidazolone derivatives(Elsevier Inc. [email protected], 2018) Aksoydan, Busecan; Kantarcioglu, Isik; Erol, Ismail; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kantarcioglu, Isik, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyAngiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. A database consisting of 3500-fragments were used to enumerate de novo designed imidazolone and oxazolone derivatives and hereby more than 50000 novel small molecules were generated. These derivatives were then used in high throughput virtual screening simulations (Glide/HTVS) to find potent hit molecules. In addition, virtual screening of around 18 million small drug-like compounds from ZINC database were screened at the binding pocket of the AT1 receptor via Glide/HTVS method. Filtered structures were then used in more sophisticated molecular docking simulations protocols (i.e., Glide/SP, Glide/XP, Glide/IFD, Glide/QPLD, and GOLD). However, the K+ ion channel/drug interactions should also be considered in studies implemented in molecular level against their cardiovascular risks. Thus, selected compounds with high docking scores via all diverse docking algorithms are also screened at the pore domain regions of human ether-a-go-go-related gene (hERG1) K+ channel to remove the high affinity hERG1 blocking compounds. High docking scored compounds at the AT1 with low hERG1 affinity is considered for long molecular dynamics (MD) simulations. Post-processing analysis of MD simulations assisted for better understanding of molecular mechanism of studied compounds at the binding cavity of AT1 receptor. Results of this study can be useful for designing of novel and safe AT1 inhibitors. © 2017 Elsevier B.V., All rights reserved.Publication Metadata only The effects of pollen, propolis, and caffeic acid phenethyl ester on tyrosine hydroxylase activity and total RNA levels in hypertensive rats caused by nitric oxide synthase inhibition: experimental, docking and molecular dynamic studies(Taylor and Francis Ltd. [email protected], 2018) Salmas, Ramin Ekhteiari; Durdagi, Serdar; Gülhan, Mehmet Fuat; Duruyurek, Merve; Abdullah, Huda Ismail; Selamoglu, Zeliha S.; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Gülhan, Mehmet Fuat, Department of Medicinal and Aromatic Plants, Vocational School of Technical Sciences, Aksaray, Turkey; Duruyurek, Merve, Department of Biotechnology, Niğde Ömer Halisdemir University, Nigde, Turkey; Abdullah, Huda Ismail, Department of Pharmacology, New York Medical College, Valhalla, United States; Selamoglu, Zeliha S., Department of Biotechnology, Niğde Ömer Halisdemir University, Nigde, TurkeyThe objective of the present study was to evaluate the effects of propolis, pollen, and caffeic acid phenethyl ester (CAPE) on tyrosine hydroxylase (TH) activity and total RNA levels of Nω-nitro-L-arginine methyl ester (L-NAME) inhibition of nitric oxide synthase in the heart, adrenal medulla, and hypothalamus of hypertensive male Sprague dawley rats. The TH activity in the adrenal medulla, heart, and hypothalamus of the rats was significantly increased in the L-NAME group vs. control (p < 0.05). Treatment with L-NAME led to a significant increase in blood pressure (BP) in the L-NAME group compared to control (p < 0.05). These data suggest that propolis, pollen, and CAPE may mediate diminished TH activity in the heart, adrenal medulla, and hypothalamus in hypertensive rats. The decreased TH activity may be due to the modulation and synthesis of catecholamines and BP effects. In addition, the binding mechanism of CAPE within the catalytic domain of TH was investigated by means of molecular modeling approaches. These data suggest that the amino acid residues, Glu429 and Ser354 of TH may play a pivotal role in the stabilization of CAPE within the active site as evaluated by molecular dynamics (MD) simulations. Gibbs binding free energy (ΔGbinding) of CAPE in complex with TH was also determined by post-processing MD analysis approaches (i.e. Poisson-Boltzmann Surface Area (MM-PBSA) method). © 2018 Elsevier B.V., All rights reserved.