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Publication Metadata only Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism(AMER CHEMICAL SOC, 2019) Ntountaniotis, Dimitrios; Andreadelis, Ioannis; Kellici, Tahsin F.; Karageorgos, Vlasios; Leonis, Georgios; Christodoulou, Eirini; Kiriakidi, Sofia; Becker-Baldus, Johanna; Stylos, Evgenios K.; Chatziathanasiadou, Maria V.; Chatzigiannis, Christos M.; Damalas, Dimitrios E.; Aksoydan, Busecan; Javornik, Uros; Valsami, Georgia; Glaubitz, Clemens; Durdagi, Serdar; Thomaidis, Nikolaos S.; Kolocouris, Antonios; Plavec, Janet; Tzakos, Andreas G.; Liapakis, George; Mavromoustakos, Thomas; National & Kapodistrian University of Athens; University of Crete; National & Kapodistrian University of Athens; Goethe University Frankfurt; University of Ioannina; University of Ioannina; National & Kapodistrian University of Athens; Bahcesehir University; National Institute of Chemistry - Slovenia; National & Kapodistrian University of AthensRenin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-beta-cyclodextrin (2-HP-beta-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state C-13 cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The C-13 CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-beta-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-beta-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.Publication Metadata only Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking(AMER CHEMICAL SOC, 2017) Salmas, Ramin Ekhteiari; Seeman, Philip; Aksoydan, Busecan; Erol, Ismail; Kantarcioglu, Isik; Stein, Matthias; Yurtsever, Mine; Durdagi, Serdar; Bahcesehir University; University of Toronto; University of Toronto; Gebze Technical University; Max Planck Society; Istanbul Technical UniversityDopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2(High)R and D2(Low)R dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2(High)R and D2(Low)R targets were -12.04 and -9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2(High)R and D2L(ow)R with binding affinities (K-i) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [H-3]domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2(High)R. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2(High)R binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2(Low)R Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as a template and screening of small-molecule databases with derived pharmacophore models.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(AMER CHEMICAL SOC, 2018) Is, Yusuf Serhat; Durdagi, Serdar; Aksoydan, Busecan; Yurtsever, Mine; Bahcesehir University; Istanbul Technical University; Bahcesehir University; Ministry of National Education - Turkey; Gedik UniversityMonoamine 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.Publication Metadata only Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor(AMER CHEMICAL SOC, 2017) Salmas, Ramin Ekhteiari; Seeman, Philip; Aksoydan, Busecan; Stein, Matthias; Yurtsever, Mine; Durdagi, Serdar; Bahcesehir University; University of Toronto; Max Planck Society; Istanbul Technical UniversityThe dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to he 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 [H-3] (+)-4-propy1-3,4,4a,5,6,10 b-hexahyd ro-2H-naphtho [1,2-b] [1,4] oxazin-9-ol ((+)PHNO) revealed K-i values of 32 nM for the D2(high)R and 52 mu M for the D2(IOW)R. The calculated binding affinities of ACRI6 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2(high)R 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 D2(high)R is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2(high)R 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.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 FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2018) Durdagi, Serdar; Aksoydan, Busecan; Erol, Ismail; Kantarcioglu, Isik; Ergun, Yavuz; Bulut, Gulay; Acar, Melih; Avsar, Timucin; Liapakis, George; Karageorgos, Viasios; Salmas, Ramin E.; Sergi, Baris; Alkhatib, Sara; Turan, Gizem; Yigit, Berfu Nur; Cantasir, Kutay; Kurt, Bahar; Kilic, Turker; Bahcesehir University; Gebze Technical University; Dokuz Eylul University; Bahcesehir University; Bahcesehir University; University of Crete; Bahcesehir University; Bahcesehir University; Bahcesehir University; Bahcesehir University; Bahcesehir UniversityAT1 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 [I-125-Sar(1)-Ile(8)] 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. (C) 2017 Elsevier Masson SAS. All rights reserved.Publication Metadata only Synthesis, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors(TAYLOR & FRANCIS LTD, 2017) Kurt, Belma Zengin; Sonmez, Fatih; Durdagi, Serdar; Aksoydan, Busecan; Salmas, Ramin Ekhteiari; Angeli, Andrea; Kucukislamoglu, Mustafa; Supuran, Claudiu T.; Bezmialem Vakif University; Sakarya University; Bahcesehir University; University of FlorenceNew 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 K-i 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.Publication Metadata only Reducing Virulence and Biofilm of Pseudomonas aeruginosa by Potential Quorum Sensing Inhibitor Carotenoid: Zeaxanthin(SPRINGER, 2017) Gokalsin, Baris; Aksoydan, Busecan; Erman, Burak; Sesal, Nuzhet Cenk; Marmara University; Bahcesehir University; Koc UniversityPseudomonas aeruginosa can regulate its virulence gene expressions by using a signal system called quorum sensing. It is known that inhibition of quorum sensing can block biofilm formation and leave the bacteria defenseless. Therefore, it is necessary to determine natural sources to obtain potential quorum sensing inhibitors. This study aims to investigate an alternative treatment approach by utilizing the carotenoid zeaxanthin to reduce the expressions of P. aeruginosa virulence factors through quorum sensing inhibition. The inhibition potential of zeaxanthin was determined by in silico screening from a library of 638 lichen metabolites. Fluorescent monitor strains were utilized for quorum sensing inhibitor screens, and quantitative reverse-transcriptase PCR assay was performed for evaluating gene expression. Results indicate that zeaxanthin is a better inhibitor than the lichen secondary metabolite evernic acid, which was previously shown to be capable of inhibiting P. aeruginosa quorum sensing systems.Publication Metadata only Identification of novel serotonin reuptake inhibitors targeting central and allosteric binding sites: A virtual screening and molecular dynamics simulations study(ELSEVIER SCIENCE INC, 2017) Erol, Ismail; Aksoydan, Busecan; Kantarcioglu, Isik; Salmas, Ramin E.; Durdagi, Serdar; Bahcesehir University; Gebze Technical UniversityThe 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. (C) 2017 Elsevier Inc. All rights reserved.Publication Metadata only Current status of multiscale simulations on GPCRs(CURRENT BIOLOGY LTD, 2019) Durdagi, Serdar; Dogan, Berna; Erol, Ismail; Kayik, Gulru; Aksoydan, Busecan; Bahcesehir University; Bahcesehir University; Gebze Technical UniversityMembrane 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.Publication Metadata only Structure-based design of hERG-neutral antihypertensive oxazalone and imidazolone derivatives(ELSEVIER SCIENCE INC, 2018) Aksoydan, Busecan; Kantarcioglu, Isik; Erol, Ismail; Salmas, Ramin Ekhteiari; Durdagi, Serdar; Bahcesehir University; Gebze Technical UniversityAngiotensin 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. (C) 2017 Elsevier Inc. All rights reserved.
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