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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 Open Access The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands(Taylor and Francis Ltd. [email protected], 2017) Salmas, Ramin Ekhteiari; Stein, Matthias Jeanette; Yurtsever, Mine; Seeman, Philip; Erol, Ismail; Mestanoglu, Mert; Durdagi, Serdar; Salmas, Ramin Ekhteiari, 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; Seeman, Philip, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada; Erol, Ismail, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, Gebze Teknik Üniversitesi, Gebze, Turkey; Mestanoglu, Mert, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyG-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction of universal pharmacophore models for D2R ligands were also studied. The key amino acids, which contributed to the regular activation of the D2R, were in detail investigated by means of normal mode analysis (NMA). A derived cross-correlation matrix provided us an understanding of the degree of pair residue correlations. Although negative correlations were not observed in the case of the inactive D2R state, a high degree of correlation appeared between the residues in the active state. NMA results showed that the cytoplasmic side of the TM5 plays a significant role in promoting of residue–residue correlations in the active state of D2R. Tracing motions of the amino acids Arg219, Arg220, Val223, Asn224, Lys226, and Ser228 in the position of the TM5 are found to be critical in signal transduction. Complementing the receptor-based modeling, ligand-based modeling was also performed using known D2R ligands. The top-scored pharmacophore models were found as 5-sited (AADPR.671, AADRR.1398, AAPRR.3900, and ADHRR.2864) hypotheses from PHASE modeling from a pool consisting of more than 100 initial candidates. The constructed models using 38 D2R ligands (in the training set) were validated with 15 additional test set compounds. The resulting model correctly predicted the pIC50 values of an additional test set compounds as true unknowns. © 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 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.