Biyoinformatik ve Genetik Bölümü Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12469/46

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Citation - WoS: 17
Citation - Scopus: 20
In Silico Design of Novel and Highly Selective Lysine-Specific Histone Demethylase Inhibitors
(Scientific Technical Research Council Turkey-Tubitak, 2011) Akdoğan, Ebru Demet; Erman, Burak; Yelekçi, Kemal
Histone lysine-specific demethylase (LSD1) is involved in a wide range of epigenetic processes and plays important roles in gene silencing DNA transcription DNA replication DNA repair and heterochromatin formation. Its active site shows a resemblance to those of 2 homologous enzymes monamine oxidase A and B (MAO-A and MAO-B.) In the present work starting from suitable scaffolds and generating thousands of structures from them 10 potential inhibitors were obtained with structural and physicochemical properties selectively suitable for inhibiting LSD1. iLib Diverse software was used to generate the diverse structures and 3 docking tools CDOCKER GOLD and AutoDock were used to find the most probable potential inhibitor based on its binding affinity. The dispositions of the candidate molecules within the organism were checked by ADMET_PSA_2D (polar surface area) versus ADMET_AlogP98 (the logarithm of the partition coefficient between n-octanol and water) and their suitability is discussed. The LSD1 inhibition activities of the candidates were compared with the properties of trans-2-phenylcyclopropylamine (tranylcypromine) and 2-(4-methoxy-phenyl) cyclopropylamine which are the 2 known inhibitors of LSD1.
Citation - WoS: 4
Citation - Scopus: 3
Drying of Polyacrylamide-Multiwalled Carbon Nanotube (mwnt) Composites With Various Mwnts Contents: a Fluorescence Study
(Walter De Gruyter Gmbh, 2013) Evingür, Gülşen Akin; Pekcan, Önder
We studied the drying of polyacrylamide (PAAm)-multiwalled carbon nanotube (MWNT) composites prepared by free radical crosslinking copolymerization in water with a steady state fluorescence technique. Composite gels were prepared at room temperature with pyranine (Py) doped as a fluorescence probe. Drying experiments were performed in air at various MWNT contents by real time monitoring of the Py fluorescence intensity (I) which increased as the drying proceeded. The Stern-Volmer equation combined with the moving boundary diffusion model was used to explain the behavior of I during drying. It was observed that the desorption coefficient (D) increased as the temperature increased. Drying energies (Delta E) were measured for the drying processes for each MWNT content gel by using fluorescence gravimetrical and volumetric methods. It is understood that Delta E values decrease by increasing MWNT content until 1 wt % MWNT and then increase above the level of this threshold value. The energy of drying is strongly correlated with the MWNT content in the composite. Delta E drops to its lowest value at which conducting cluster starts to appear.
Citation - WoS: 6
Citation - Scopus: 6
Temperature Effect on the Swelling of Paam-Kappa Composites
(Wiley-Blackwell, 2012) Evingür, Gülşen Akin; Pekcan, Önder
The steady-state fluorescence (SSF) technique was used for studying swelling of disc-shaped polyacrylamide (PAAm)-kappa-carrageenan (kappa C) composites which were prepared by free-radical crosslinking copolymerization at 80 degrees C. Pyranine was introduced as a fluorescence probe during polymerization. Swelling experiments were performed in water at various temperatures by real-time monitoring of the pyranine (Py) fluorescence intensity I which decreased as swelling proceeded. Stern-Volmer equation is modified for low quenching efficiencies to interpret the behavior of Py intensity during the swelling of PAAm-kappa C composites. The Li-Tanaka equation was used to determine the swelling time constants tau(1) and cooperative diffusion coefficients D(0) from fluorescence intensity weight and volume variations of the composites at various temperatures. It was observed that tau(1) first decreased up to 40 degrees C and then increased
Citation - WoS: 6
Citation - Scopus: 6
Study of Thermal Phase Transitions in Iota Carrageenan Gels Via Fluorescence Technique
(Wiley-Blackwell, 2011) Tari, Ozlem; Kara, Selim; Pekcan, Önder
The effect of carrageenan concentration on thermal phase transitions of the iota carrageenan gels was investigated by using fluorescence technique. During heating and cooling processes scattered light I(sc) and fluorescence intensity I(p) were monitored against temperature to investigate phase transitions. Transition temperatures from the derivative of the transition paths were determined. Two regions were observed during the heating and cooling processes. At the first step of the heating dimers were converted into double helix by undergoing dimer to double helix (d-h) transition. At the higher temperature region double helix to coil (h-c) transition took place. During the cooling process these transitions are arranged in the order of coil to double helix (c-h) and double helix to dimer (h-d). A hysteresis was observed between (h-d) and (d-h) transitions. The critical gel fraction exponents beta were found to be independent of the system by indicating that they all fall into the same universality class. (C) 2011 Wiley Periodicals Inc. J Appl Polym Sci 121: 2652-2661 2011
Citation - WoS: 15
Citation - Scopus: 17
Crystallographic Structure Versus Homology Model: a Case Study of Molecular Dynamics Simulation of Human and Zebrafish Histone Deacetylase 10
(Taylor & Francis, 2020) Uba, Abdullahi İbrahim; Yelekçi, Kemal
Histone deacetylase (HDAC) 10 has been implicated in the pathology of various cancers and neurodegenerative disorders, making the discovery of novel inhibitors of the isoform an important endeavor. However, the unavailability of crystallographic structure of human HDAC10 (hHDAC10) hinders structure-based drug design effort. Previously, we reported the homology modeled structure of human HDAC10 built using the crystallographic structure of Danio rerio (zebrafish) HDAC10 (zHDAC10) (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) as a template. Here, in continuation with our study, both hHDAC10 and zHDAC10, and their respective complexes with trichostatin A (TSA), quisinostat, and the native ligand (in 5TD7), 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptane-2,2-diol (PDB ID; FKS) were submitted to 100 ns-long unrestrained molecular dynamics (MD) simulations. Comparative analyses of the MD trajectories revealed that zHDAC10 and its complexes displayed higher stability than hHDAC10 and its corresponding complexes over time. Nonetheless, docking of active and inactive set molecules revealed that more reliable conformations of hHDAC10 could be obtained at an extended time period. This study may shed more light on the reliability of hHDAC10 modeled structure for use in selective inhibitor design.Communicated by Ramaswamy H. Sarma.
Citation - WoS: 11
Citation - Scopus: 14
Effect of Multiwalled Carbon Nanotube (mwnt) on the Behavior of Swelling of Polyacrylamide-Mwnt Composites
(Sage Publications Ltd, 2014) Evingür, Gülşen Akin; Pekcan, Önder
The purpose of this paper is to discuss the role of multiwalled carbon nanotube in the swelling of polyacrylamide-multiwalled carbon nanotube composites. Swelling experiments were performed in water at various temperatures by real-time monitoring of the decrease in pyranine (Py) and emission light intensity (I-em). The Stern-Volmer equation is modified for low-quenching efficiencies to interpret the behavior of pyranine intensity during the swelling of polyacrylamide-multiwalled carbon nanotube composites. The Li-Tanaka equation was used to determine the swelling time constants tau and cooperative diffusion coefficients D from fluorescence intensity weight and volume variations of the composite at various temperatures. It was observed that when tau decreased naturally D increased by increasing temperatures.
Docking-Based Virtual Screening for Potential Activity Against Bacterial Pyruvate Kinase
(Springer, 2017) Ergün, Çağla; Akten, Ebru Demet; Doruker, Pemra
[Abstract Not Available]
Citation - WoS: 3
Citation - Scopus: 3
The Neural Gamma(2)alpha(1)beta(2)alpha(1)beta(2) Gamma Amino Butyric Acid Ion Channel Receptor: Structural Analysis of the Effects of the Ivermectin Molecule and Disulfide Bridges
(Springer, 2018) Ayan, Meral; Eşsiz, Şebnem
While similar to 30% of the human genome encodes membrane proteins only a handful of structures of membrane proteins have been resolved to high resolution. Here we studied the structure of a member of the Cys-loop ligand gated ion channel protein superfamily of receptors human type A gamma(2)alpha(1)beta(2)alpha(1)beta(2) gamma amino butyric acid receptor complex in a lipid bilayer environment. Studying the correlation between the structure and function of the gamma amino butyric acid receptor may enhance our understanding of the molecular basis of ion channel dysfunctions linked with epilepsy ataxia migraine schizophrenia and other neurodegenerative diseases. The structure of human gamma(2)alpha(1)beta(2)alpha(1)beta(2) has been modeled based on the X-ray structure of the Caenorhabditis elegans glutamate-gated chloride channel via homology modeling. The template provided the first inhibitory channel structure for the Cys-loop superfamily of ligand-gated ion channels. The only available template structure before this glutamate-gated chloride channel was a cation selective channel which had very low sequence identity with gamma aminobutyric acid receptor. Here our aim was to study the effect of structural corrections originating from modeling on a more reliable template structure. The homology model was analyzed for structural properties via a 100 ns molecular dynamics (MD) study. Due to the structural shifts and the removal of an open channel potentiator molecule ivermectin from the template structure helical packing changes were observed in the transmembrane segment. Namely removal of ivermectin molecule caused a closure around the Leu 9 position along the ion channel. In terms of the structural shifts there are three potential disulfide bridges between the M1 and M3 helices of the gamma(2) and 2 alpha(1) subunits in the model. The effect of these disulfide bridges was investigated via monitoring the differences in root mean square fluctuations (RMSF) of individual amino acids and principal component analysis of the MD trajectory of the two homology models-one with the disulfide bridge and one with protonated Cys residues. In all subunit types RMSF of the transmembrane domain helices are reduced in the presence of disulfide bridges. Additionally loop A loop F and loop C fluctuations were affected in the extracellular domain. In cross-correlation analysis of the trajectory the two model structures displayed different coupling in between the M2-M3 linker region protruding from the membrane and the beta 1-beta 2/D loop and cys-loop regions in the extracellular domain. Correlations of the C loop which collapses directly over the bound ligand molecule were also affected by differences in the packing of transmembrane helices. Finally more localized correlations were observed in the transmembrane helices when disulfide bridges were present in the model. The differences observed in this study suggest that dynamic coupling at the interface of extracellular and ion channel domains differs from the coupling introduced by disulfide bridges in the transmembrane region. We hope that this hypothesis will be tested experimentally in the near future.
Citation - WoS: 7
Citation - Scopus: 8
Design, Synthesis and in Vitro Cytotoxic Activity of New 6,9-Disubstituted Purine Analogues
(Slovensko Kemijsko Drustvo, 2020) Kuçükdumlu, Aslıgül; Tunçbilek, Meral; Bilget Güven, Ebru; Atalay, Rengül Çetin
A series of new 6,9-disubstituted purine analogs with 4-substituted piperazine at C-6 and 4-substituted benzyl at N-9 were designed and synthesized in four steps. All synthesized compounds (7-26) were screened initially for their in vitro anticancer activity on Huh7 liver, HCT116 colon and MCF7 breast carcinoma cell lines. Cytotoxic bioactivity studies revealed that all compounds screened, with compound 19 being the exception, were found to have promising cytotoxic activities at IC50 range of 0.05-21.8 mu M against cancer cells Huh7, HCT116 and MCF7. Among the prepared purine analogs, two of them (12 and 22) exhibited excellent cytotoxic activities, with IC50 0.08-0.13 mu M, on Huh7 cells comparable to camptothecin (CPT) and better than cladribine, fludarabine and 5-FU. Afterwards, the evaluation of cytotoxicity of the most potent purine analogs was screened against further hepatocellular cancer (HCC) cell lines. The 6-(4-(4-trifluoromethylphenyl)piperazine (12) and 6-(4-(3,4-dichlorophenyl)piperazine analogs (25) displayed a significant IC50 values (IC50 < 0.1-0.13 mu M) comparable to CPT and better cytotoxic bioactivity when compared with 5-FU, cladribine and fludarabine on HCC cells (Huh7 and HepG2).
Citation - WoS: 12
Citation - Scopus: 14
Elastic Percolation of Swollen Polyacrylamide (paam)-Multiwall Carbon Nanotubes Composite
(Taylor & Francis Ltd, 2012) Evingür, Gülşen Akin; Pekcan, Önder
Polyacrylamide (PAAm)-multiwalled carbon nanotube (MWNT) composites were prepared via free radical cross-linking copolymerization with different amounts of MWNTs varying in the range between 0.1 and 50 wt%. The mechanical properties of swollen PAAm-MWNT composites were characterized by the tensile testing technique. A small content of embedded nanotubes dramatically changes the compressive elastic modulus of the composites. Compressive elastic modulus dramatically increases up to 1wt% MWNT on increasing nanotube content and then decreases presenting a critical MWNT value indicating that there is a sudden change in the material elasticity. The critical exponent y of elasticity below the critical MWNT content 1 wt% is found to be 0.58 which is consistent with the suggestions of percolation in the superelastic percolation network for PAAm-MWNT composite.
Citation - WoS: 4
Citation - Scopus: 3
Electrical Optical and Fluorescence Percolations in P(vac-co-bua)/Mwcnt Composite Films
(Taylor & Francis Ltd, 2013) Arda, Ertan; Kara, Selim; Pekcan, Önder
Effects of multiwall carbon nanotube (MWCNT) addition on the electrical conductivities optical transparencies and fluorescence emissions of poly(vinyl acetate-co-butyl acrylate) (P(VAc-co-BuA))/MWCNT composite films were studied. Optical transmission fluorescence emission and two point probe resistivity techniques were used to determine the variations of the optical fluorescence and electrical properties of the composites respectively. Transmitted photon intensity (I-tr) fluorescence emission intensity (I-fl) and surface resistivity ((s)) of the composite films were monitored as a function of MWCNT mass fraction (M) at room temperature. All these measured quantities of the composites were decreased by increasing the content of MWCNT in the composite. The conductivity and the optical results were attributed to the classical and site percolation theories respectively. The fluorescence results however possessed both the site and classical percolation theories at low and high MWCNT content regions respectively.
Investigation of Intrinsic Dynamics and Allosteric Coupling in Human Beta 2-Adrenergic Receptor
(Springer, 2017) Özcan, Özer; Özgür, Canan; Doruker, Pemra; Akten, Ebru Demet
[Abstract Not Available]
Citation - WoS: 8
Citation - Scopus: 9
Human Dopamine Transporter: the First Implementation of a Combined in Silico/In Vitro Approach Revealing the Substrate and Inhibitor Specificities
(Taylor & Francis Inc, 2019) Djikic, Teodora; Marti, Yasmina; Spyrakis, Francesca; Lau, Thorsten; Benedetti, Paolo; Davey, Gavin; Schloss, Patrick; Yelekçi, Kemal
Parkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine thereby enhancing and compensating a loss of dopaminergic neurotransmission and to exert neuroprotective response because of their accumulation in the cytoplasm are required. By means of homology modeling molecular docking and molecular dynamics simulations we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake through in vitro live cell imaging experiments. Taken together our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.
Citation - WoS: 4
Citation - Scopus: 5
Kinetic Models for the Dynamical Behavior of Polyacrylamide (paam)-Kappa (kappa C) Composite Gels
(Springer, 2015) Evingür, Gülşen Akın; Pekcan, Önder
A fluorescence method was employed for studying the drying and swelling of PAAm-kappa C composite gels which were formed from acrylamide (AAm) and N N'- methylenebisacrylamide (BIS) with various kappa-carrageenan (kappa C) contents by free radical crosslinking copolymerization in water. Composite gels were prepared at 80 A degrees C with pyranine (Py) as a fluorescence probe. Scattered light I (sc) and fluorescence emission intensities I (em) were monitored during drying and swelling of these gels. The fluorescence intensity of pyranine increased and decreased as drying and swelling time are increased respectively for all gel samples. The Stern-Volmer equation combined with moving boundary and Li-Tanaka models were used to explain the behavior of I (em) during drying and swelling processes respectively. It is found that the desorption coefficient D (d) decreased as kappa C contents were increased for a given temperature during drying. However the cooperative diffusion coefficient D (s) presented exactly the opposite case. Conventional gravimetrical and volumetric experiments were also carried out during drying and swelling of PAAm-kappa C composite gels. It was observed that D (d) and D (s) values measured with the fluorescence method were found to be much larger than they were measured with the conventional methods.
Citation - WoS: 26
Citation - Scopus: 31
Homology Modeling of Human Histone Deacetylase 10 and Design of Potential Selective Inhibitors
(Taylor & Francis Inc, 2019) Uba, Abdullahi Ibrahim; Yelekçi, Kemal
Histone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score-a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization. Communicated by Ramaswamy H. Sarma
Citation - WoS: 6
Citation - Scopus: 8
The Design of Potent Hiv-1 Integrase Inhibitors by a Combined Approach of Structure-Based Virtual Screening and Molecular Dynamics Simulation
(Taylor & Francis Ltd, 2018) Samorlu, Augustine S.; Yelekçi, Kemal; Uba, Abdullahi Ibrahim
Bu araştırmanın amacı, AIDS olarak bilinen insan bağışıklık sistemine etki eden, duraksamayan ve depresif bir hastalığa neden olan HIV-1'in tedavisi için potansiyel inhibitörleri elde etmektir. HIV-1 integraz inhibitörleri, HIV-1 enfeksiyonunun tedavisinde çok önemlidir. İntegraz enziminin (IN) inhibe edilmesi HIV-1 virüsünün çoğalma işleminin sonlandırılmasına neden olur. Böylece yaşam döngüsüne son verir. Bu inhibitörleri elde etmek için bilgisayar destekli in silico yaklaşım kullanılmıştır. Temelde, Otava Kimya Kütüphanesi tarandı ve inhibitör tasarımında kullanılan sistematik yaklaşımlar uygulandı, böylece dört güçlü integraz inhibitörü bulundu. İnhibitörlerin enzime bağlanma değerleri PyRx ve AutoDock 4.2 doklama programları kullanılarak gerçekleştirildi. Çalışmada bir kimyasalın güçlü bir inhibitör olabilmesi için hesaplanan serbest bağ enerjisi = -8.00 kcal / mol veya daha az olması ve integrazın aktif bölgesinde bulunan 3 önemli amino asidinden herhangi biri ile de etkileşimde bulunması kriterine uyulmuştur. Discovery Studio Visualizer, inhibitörlerin yapısını çizmekte, inhibitörü komplekslerinin resimlerini üretmekte, enzim ve inhibitör arasındaki etkileşimin türünü belirlememizi sağlayan 2D ve 3D yapıları görüntülemek için kullanıldı. Elde edilen dört güçlü inhibitörden, kendimizin tasarladığı moleküllerden (Ki= 652.83 nanomolar bir ve bağlanma serbest enerjisi -8.44kcal / mol), kalan üç inhibitörde, Otava Kimya Kütüphanesi'nde tarandı ve Otava koduyla parantez içerisinde listelenmiştir. Bunların inhibisyon sabiti ve bağlanma enerjileri sırasıyla; 107320240, Ki=131.7nm, -9.39kcal/ mol; 109750115, Ki= 44.19nm, -10.03kcal / mol; 111150115 Ki = 395.19nm, -8.74kcal / mol olarak bulunmuştur.
Citation - WoS: 3
Citation - Scopus: 3
Transmembrane Helix 6 Observed at the Interface of Beta(2)ar Homodimers in Blind Docking Studies
(Taylor & Francis Inc, 2015) Koroğlu, Ayça; Akten, Ebru Demet
Peptide- and protein-protein dockings were carried out on beta(2)-adrenergic receptor (beta(2)AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two beta(2)AR monomers thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to beta(2)AR monomer using a rigid body approach. Interestingly all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore longer peptides generated from a whole TM region were blindly docked to beta(2)AR using the same rigid body approach. This yielded a total of seven docked peptides each derived from one TM helix. Most interestingly for each peptide TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings two beta(2)AR monomers were blindly docked to each other using a full rigid-body search of docking orientations which yielded a total of 16000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements 102 conformers were composed of two monomers oriented in opposite directions whereas in the remaining 47 the monomers were arranged in parallel. Lastly all 149 conformers were clustered based on a root mean-squared distance value of 6 angstrom. In agreement with the peptide results the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.
Citation - WoS: 2
Citation - Scopus: 3
Mapping the Two-Component Atomic Fermi Gas To the Nuclear Shell-Model
(Springer, 2014) Özen, Cem; Zinner, Nikolaj Thomas
The physics of a two-component cold Fermi gas is now frequently addressed in laboratories. Usually this is done for large samples of tens to hundreds of thousands of particles. However it is now possible to produce few-body systems (1-100 particles) in very tight traps where the shell structure of the external potential becomes important. A system of two-species fermionic cold atoms with an attractive zero-range interaction is analogous to a simple model of nucleus in which neutrons and protons interact only through a residual pairing interaction. In this article we discuss how the problem of a two-component atomic Fermi gas in a tight external trap can be mapped to the nuclear shell-model so that readily available many-body techniques in nuclear physics such as the Shell-Model Monte Carlo (SMMC) method can be directly applied to the study of these systems. We demonstrate an application of the SMMC method by estimating the pairing correlations in a small two-component Fermi system with moderate-to-strong short-range two-body interactions in a three-dimensional harmonic external trapping potential.
Citation - WoS: 1
Citation - Scopus: 1
Exploring Distinct Binding Site Regions of Beta(2)-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Scientific Technical Research Council Turkey-Tubitak, 2013) Cakan, Sibel; Akdoğan, Ebru Demet
beta(2)-Adrenergic receptor (beta(2)AR) is a G protein-coupled receptor that is highly flexible and able to recognize a wide range of ligands through its conformational variations. Active and inactive conformations revealed by recent crystallographic experiments do not provide a complete dynamic picture of the receptor especially in the binding site. In this study molecular dynamics (MD) simulation through a residue-based coarse-grained model is used as an alternative and efficient method to explore a wider conformational search space. The system was composed of beta(2)AR embedded into a 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane bilayer with surrounding water. A total of 6 mu s of simulation at constant NPT was performed for a system of 6868 coarse-grained beads. The system reached equilibrium at around 0.1 mu s. The overall 3-dimensional structure was well preserved throughout the simulation. Local residue-based fluctuations were in good agreement with fully atomistic MD simulations. Four distinct snapshots were selected and reverse-mapped to all-atom representations with around 65000 atoms. Each reverse-mapped system was later subjected to 100 ns of MD simulation for equilibration. Root mean square deviation clustering analysis yielded distinct receptor conformers for the binding site regions which were suggested to be alternative representations of the binding pocket and thus were proposed as plausible targets in docking-based virtual screening experiments for the discovery of novel antagonists.
Citation - WoS: 12
Citation - Scopus: 13
Homology Modeling Andin Silicodesign of Novel and Potential Dual-Acting Inhibitors of Human Histone Deacetylases Hdac5 and Hdac9 Isozymes
(2020) Elmezayen, Ammar D.; Yelekçi, Kemal
Histone deacetylases (HDACs) are a group of enzymes that have prominent and crucial effect on various biological systems, mainly by their suppressive effect on transcription. Searching for inhibitors targeting their respective isoforms without affecting other targets is greatly needed. Some histone deacetylases have no crystal structures, such as HDAC5 and HDAC9. Lacking proper and suitable crystal structure is obstructing the designing of appropriate isoform selective inhibitors. Here in this study, we constructed human HDAC5 and HDAC9 protein models using human HDAC4 (PDB:2VQM_A) as a template by the means of homology modeling approach. Based on the Z-score of the built models, model M0014 of HDAC5 and model M0020 of HDAC9 were selected. The models were verified by MODELLER and validated using the Web-based PROCHECK server. All selected known inhibitors displayed reasonable binding modes and equivalent predicted Ki values in comparison to the experimental binding affinities (Ki/IC50). The known inhibitor Rac26 showed the best binding affinity for HDAC5, while TMP269 showed the best binding affinity for HDAC9. The best two compounds, CHEMBL2114980 and CHEMBL217223, had relatively similar inhibition constants against HDAC5 and HDAC9. The built models and their complexes were subjected to molecular dynamic simulations (MD) for 100 ns. Examining the MD simulation results of all studied structures, including the RMSD, RMSF, radius of gyration and potential energy suggested the stability and reliability of the built models. Accordingly, the results obtained in this study could be used for designing de novo inhibitors against HDAC5 and HDAC9. Communicated by Ramaswamy H. Sarma

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