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Publication Open Access Synthesis, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors(Taylor and Francis Ltd [email protected], 2017) Zengin Kurt, Belma; Sönmez, Fatih; Durdagi, Serdar; Aksoydan, Busecan; Salmas, Ramin Ekhteiari; Angeli, Andrea; Küçükislamoǧlu, Mustafa; Supuran, Claudiu T.; Zengin Kurt, Belma, Department of Pharmaceutical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Sönmez, Fatih, Department of Chemistry, Sakarya Üniversitesi, Serdivan, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Angeli, Andrea, Dipartimento Neurofarba, Università degli Studi di Firenze, Florence, Italy; Küçükislamoǧlu, Mustafa, Department of Chemistry, Sakarya Üniversitesi, Serdivan, Turkey; Supuran, Claudiu T., Dipartimento Neurofarba, Università degli Studi di Firenze, Florence, ItalyNew coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-N-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-2H-chromene-3-carboxamide (e11) exhibited a selective inhibitory action against hCA IX with the Ki of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms. © 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 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 Application of multiscale simulation tools on GPCRs. An example with angiotensin II type 1 receptor(Humana Press Inc. [email protected], 2018) Erol, Ismail; Aksoydan, Busecan; Kantarcioglu, Isik; Durdagi, Serdar; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kantarcioglu, Isik, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyG protein-coupled receptors (GPCRs) represent the biggest class of membrane proteins included in signal transduction cascade across the biological lipid bilayers. They are essential target structures for cell signaling and are of great commercial interest to the pharmaceutical industry (~50% of marketed drugs and ~25% of top-selling drugs targeting this receptor family). Recent advances made in molecular biology and computational chemistry open new avenues for the design of new therapeutic compounds. Molecular biology has recently provided the crystal structures of a few ligand-bound GPCRs in active and inactive states, which can be used as accurate templates in modeling studies. Computational chemistry offers a range of simulation, multiscale modeling with ligand- and structure-based approaches, and virtual screening tools for definition and analysis of protein-ligand, protein-protein, and protein-DNA interactions. Development of new approaches and algorithms on statistical methods and free energy simulations help to predict novel optimal compounds. Integrated approach to drug discovery that combines quantum mechanics calculations, molecular docking, molecular dynamics (MD) simulations, quantitative structure-activity relationships (QSAR), and de novo design studies under a single umbrella can be used for decreasing the risk of false-positive results. Each method has its own pros and cons and, when used alone, is not likely to yield very useful results. However, when these methods are combined with positive feedback loops, they may enhance each other and successful drug leads may be obtained. Moreover, investigating the activation mechanisms and atomistic determinants of ligand binding to GPCR targets would allow greater safety in the human life. © 2019 Elsevier B.V., All rights reserved.Publication Metadata only Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation(Elsevier Masson s.r.l., 2018) Durdagi, Serdar; Aksoydan, Busecan; Erol, Ismail; Kantarcioglu, Isik; Ergün, Yavuz; Bulut, Gulay; Acar, Melih; Avşar, Timuçin; Liapakis, George; Karageorgos, Vlasios; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Kantarcioglu, Isik, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Bioengineering Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ergün, Yavuz, Department of Chemistry, Dokuz Eylül Üniversitesi, Izmir, Turkey; Bulut, Gulay, Department of Molecular Biology and Genetics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Acar, Melih, Department of Biology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Avşar, Timuçin, Department of Biology, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Liapakis, George, Department of Pharmacology, University of Crete, Rethymnon, Greece; Karageorgos, Vlasios, Department of Pharmacology, University of Crete, Rethymnon, GreeceAT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents – due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches 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. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [125I-Sar1-Ile8] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Proposing Novel MAO-B Hit Inhibitors Using Multidimensional Molecular Modeling Approaches and Application of Binary QSAR Models for Prediction of Their Therapeutic Activity, Pharmacokinetic and Toxicity Properties(American Chemical Society [email protected], 2018) İş, Yusuf Serhat; Durdagi, Serdar; Aksoydan, Busecan; Yurtsever, Mine; İş, Yusuf Serhat, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey, Department of Chemical Technology, Gedik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, TurkeyMonoamine oxidase (MAO) enzymes MAO-A and MAO-B play a critical role in the metabolism of monoamine neurotransmitters. Hence, MAO inhibitors are very important for the treatment of several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, 256 750 molecules from Otava Green Chemical Collection were virtually screened for their binding activities as MAO-B inhibitors. Two hit molecules were identified after applying different filters such as high docking scores and selectivity to MAO-B, desired pharmacokinetic profile predictions with binary quantitative structure-activity relationship (QSAR) models. Therapeutic activity prediction as well as pharmacokinetic and toxicity profiles were investigated using MetaCore/MetaDrug platform which is based on a manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism, and toxicity information. Particular therapeutic activity and toxic effect predictions are based on the ChemTree ability to correlate structural descriptors to that property using recursive partitioning algorithm. Molecular dynamics (MD) simulations were also performed to make more detailed assessments beyond docking studies. All these calculations were made not only to determine if studied molecules possess the potential to be a MAO-B inhibitor but also to find out whether they carry MAO-B selectivity versus MAO-A. The evaluation of docking results and pharmacokinetic profile predictions together with the MD simulations enabled us to identify one hit molecule (ligand 1, Otava ID: 3463218) which displayed higher selectivity toward MAO-B than a positive control selegiline which is a commercially used drug for PD therapeutic purposes. © 2018 Elsevier B.V., All rights reserved.Publication Metadata only Current status of multiscale simulations on GPCRs(Elsevier Ltd, 2019) Durdagi, Serdar; Doğan, Berna; Erol, Ismail; Kayık, Gülru; Aksoydan, Busecan; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Doğan, Berna, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Kayık, Gülru, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, TurkeyMembrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptors (GPCRs) represent the largest class of membrane proteins involved in signal transduction across the biological membranes. They are essential targets for cell signaling and are of great commercial interest to the pharmaceutical industry. Recent advances made in molecular biology and computational chemistry offer a range of simulation and multiscale modeling tools for the definition and analysis of protein–ligand, protein–protein, and protein–membrane interactions. The development of new techniques on statistical methods and free energy simulations help to predict novel optimal ligands, G protein specificity and oligomerization. The identification of the ligand-binding activation mechanisms and atomistic determinants as well as the interactions of intracellular binding partners that bind to GPCR targets in different coupling states will provide greater safety in human life. In this review, recent approaches and applications of multiscale simulations on GPCRs were highlighted. © 2019 Elsevier B.V., All rights reserved.Publication Metadata only Oligomerization and cooperativity in GPCRs from the perspective of the angiotensin AT1 and dopamine D2 receptors(Elsevier Ireland Ltd, 2019) Durdagi, Serdar; Erol, Ismail; Salmas, Ramin Ekhteiari; Aksoydan, Busecan; Kantarcioglu, Isik; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, 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; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kantarcioglu, Isik, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Bioengineering Program, Bahçeşehir Üniversitesi, Istanbul, TurkeyG Protein-Coupled Receptors (GPCRs) can form homo- and heterodimers or constitute higher oligomeric clusters with other heptahelical GPCRs. In this article, multiscale molecular modeling approaches as well as experimental techniques which are used to study oligomerization of GPCRs are reviewed. In particular, the effect of dimerization/oligomerization to the ligand binding affinity of individual protomers and also on the efficacy of the oligomer are discussed by including diverse examples from the literature. In addition, possible allosteric effects that may emerge upon interaction of GPCRs with membrane components, like cholesterol, is also discussed. Investigation of these above-mentioned interactions may greatly contribute to the candidate molecule screening studies and development of novel therapeutics with fewer adverse effects. © 2021 Elsevier B.V., All rights reserved.