Browsing by Author "Yelekçi, Kemal"

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Citation - WoS: 22
Citation - Scopus: 21
Synthesis Anticancer Activity and Molecular Modeling of Etodolac-Thioether Derivatives as Potent Methionine Aminopeptidase (type Ii) Inhibitors
(Wiley, 2018) Çoruh, Işıl; Çevik, Ozge; Yelekçi, Kemal; Djikic, Teodora; Küçükgüzel, Şükriye Güniz
A series of (RS)-1-{[5-(substituted)sulfanyl-4-substituted-4H-124-triazole-3-yl]methyl}-18-diethyl-1349-tetrahydropyrano[34-b]indoles (5a-v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (RS)-5-[(18-diethyl-1349-tetrahydropyrano[34-b]indole-1-yl)methyl]-4-substituted-24-dihydro-3H-124-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) colorimetric method against VERO HEPG2 (human hepatocellular liver carcinoma) SKOV3 (ovarian carcinoma) MCF7 (human breast adenocarcinoma) PC3 and DU145 (prostate carcinoma) cells at 10(-5)M (10M) for 24h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50=7.22 and 5.10M respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k 5s and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50=8.18 3.10 and 4.00M respectively) and did not display cytotoxicity. Moreover these compounds were evaluated for caspase-3 -9 and -8 protein expression and activation in the apoptosis pathway for 6 12 and 24h which play a key role in the treatment of cancer. In this study we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.
In Silico Screening of Multi Target Drug for Alzheimer'sdisease and Parkinson's Disease Using Pharmacophore-Baseddrug Discovery Approach
(Kadir Has Üniversitesi, 2019) Raji, Sarah Mohammed Jaafar; Yelekçi, Kemal
Research on neurodegenerative diseases (NDD), commonly known as Alzheimer's and Parkinson's disease are the most important concern in this aging society. Among the other causes the main suspected reasons are the production and precipitation of the beta amyloid plaques as well as the decrease of acetyl and butyryl choline neurotransmitter in the brain. This eventually results in dementia in older people. APOE (apolipoprotein) alleles (genes) are very important for the genetic determination of Alzheimer disease (AD). Those individuals carrying APOE ε4 allele have the high risk of getting AD comparing with the people having more common ε3 and ε2 alleles. MK-8931(secretase inhibitor), CSP-1103, Pioglitazone, Saracatinib, Aducanumab, Solanezumab, etc. are the drugs generally categorized as disease-modifying drugs which help to postpone the symptoms. However, modifying drugs can entirely reduce the possibility of Alzheimer disease (AD) evolution. Whereas, Parkinson's disease (PD) is a type of degenerative disorder which occurs in the central nervous system (CNS) that mainly influence the motor system. Mutations in specific genes like SNCA, LRRK2, GBA, PRKN, PINK1, PARK7, etc. are the reason for about 5-10& \%\ of PD cases. In this study, we are aiming to obtain some more potent novel inhibitors than that of the current approved drugs for Alzheimer's (target enzyme acetylcholine esterase enzyme pdb code: 1EVE) and Parkinson's disease (target enzyme monoamine oxidase enzyme pdb code: 2V5Z) using molecular modeling and in silico screening methods. Molecular modeling and docking studies are performed in this research to obtain the preferable candidates have inhibitory effect against both diseases. Wherefore, pharmacophore approach was applied by using zinc pharma database compounds to achieve the aim of this study. After several screening analysis techniques, cross docking procedure was applied on the final 15 compounds that obtained from (AD) and (PD). All compounds shown a significant binding energy with target protein, 12 compounds have had a dual effecting on both diseases and only 3 compounds were identified a selectivity against 1EVE target of acetylcholinesterase enzyme. Eventually all compounds were subjected to ADME assay and Toxicity by using ADMET SAR tool.
Targeting Cancer Epigenetic Modifiers: the Design of Isoform-Selective Histone Deacetylase Inhibitors
(Kadir Has Üniversitesi, 2018) Uba, Abdullahi İbrahim; Yelekçi, Kemal
Epigenetic alterations are believed to be the common hallmark of human cancers. Histone deacetylase (HDAC) inhibitors have proven to be effective in cancer cases where HDACs are up-regulated. However lack of selectivity of many of the HDAC inhibitors in clinical use and those at various stages of preclinical and clinical trials causes toxicity to the normal cells. it is believed that the continuous identification of isoform-selective HDAC inhibitors can eliminate this adverse effect — a task that remains particularly challenging due to the high sequence and structural conservations around the active site of HDAC isoforms. The original contribution of this study was analyzing the similarity among class i HDACs (1 2 3 and 8) and class iib HDACs (6 and 10) by sequence and structural alignments catalytic channel extraction and identification of catalytically essential amino acid residues. in addition homology model of human HDAC10 was built using a recently-released X-ray crystal structure of Danio rerio (zebrafish) HDAC10 as a template. Using these data isoform-selective HDAC inhibitors were designed by topology-based scaffold hopping structure- and ligand-based virtual screening. The top inhibitors (in terms of both binding affinity and selectivity) were subjected to structure-based in silico absorption distribution metabolism elimination and toxicity (ADMET) prediction which showed their druglikeness. Furthermore their docking complexes were submitted to molecular dynamics (MD) simulations to examine the stability of ligand binding modes. These potential isoform-selective HDAC inhibitors showed stable binding mode over time of the simulation. They can therefore serve as drug candidates or viable lead compounds for further modeling-based and experimental optimization towards the design of safe potent and selective HDAC inhibitors.
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.
In Silico Design of Novel and Highly Selective Cyclooxygenase-2 Inhibitors
(Kadir Has Üniversitesi, 2014) Mehmetoğlu, Tuğba; Yelekçi, Kemal
For many years, prevention of inflammation is achieved by inhibition of both cyclooxygenase (COX) enzymes; the eventual outcome is gastrointestinal toxicity. Selective inhibitor design for COX-2 initialized just after discovery of two distinct types of COX enzymes. Both isoforms of COX show great similarities at the active sites. It is still essential to find more potent, more selective and reversible COX-2 inhibitors. Crystallographic structures of COX-1 (pdb code: 1Q4G; Ovis aries COX-1 crystallized with Alpha-Methyl-4-Biphenylacetic, resolution 2.00 Å) and COX-2 (pdb code: 3NT1; Mus musculus COX-2 crystallized with naproxen, resolution 1.73 Å) isozymes have paved the way for computational modeling. In the present work, from receptor cavities of enzyme, suitable scaffolds for both isozyme are generated by using ZINCv12 fragment library. Accelrys 3.1's Discovery Studio Protocols and de novo design module were assigned in the derivation process of the scaffolds via link library to produce 1129 analogs. GOLD and AutoDock 4 are used to scan and define poses in catalytic sites of both COX isozymes. Known inhibitors were taken as a reference for verification of modeling studies. The best resultant inhibitors are subjected to ADMET test and validity is confirmed.
Citation - WoS: 60
Citation - Scopus: 57
Docking Studies on Monoamine Oxidase-B Inhibitors: Estimation of Inhibition Constants (k-I) of a Series of Experimentally Tested Compounds
(Pergamon-Elsevier Science Ltd, 2005) Toprakçı, Mustafa; Yelekçi, Kemal
Monoamine oxidase (EC1.4.3.4
Citation - WoS: 33
Citation - Scopus: 33
New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors
(AMER CHEMICAL SOC, 2021) Salgın-Göksen, Umut; Telli, Gökçen; Erikci, Açelya; Dedecengiz, Ezgi; Tel, Banu Cahide; Kaynak, F. Betül; Yelekçi, Kemal; Ücar, Gülberk; Gökhan-Kelekçi, Nesrin
Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted- 2-benzoxazolinone-3-yl)-acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 mu M, Selectivity Index (SI): 9.70 x 10(-4)), 7 (0.009 mu M, SI: 4.55 x 10(-5)), 14 (0.001 mu M, SI: 8.00 x 10(-4)), 21 (0.009 mu M, SI: 1.37 x 10(-5)), and 42 (0.010 mu M, SI: 5.40 x 10(-6)), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.
Citation - WoS: 11
Citation - Scopus: 20
Evaluation of Selective Human Mao Inhibitory Activities of Some Novel Pyrazoline Derivatives
(SPRINGER WIEN, 2013) Salgin-Goksen, Umut; Yabanoglu-Ciftci, Samiye; Ercan, Ayse; Yelekçi, Kemal; Ucar, Gulberk; Gokhan-Kelekçi, Nesrin
A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-35-diaryl-45-dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses IR H-1 NMR and ESI-MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined compounds 5ae 5af and 5ag were more selective than moclobemide with respect to the K (i) values experimentally found. In addition the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae-5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking.
Structure Prediction of Tb Rpob and Its Mutations Binding Analysis
(Kadir Has Üniversitesi, 2012) Dinçer, Erçin; Yelekçi, Kemal
Today, tuberculosis is a disease that is still in high-risk categories. Rifampicin is a drug that’s used commonly in the treatment of TB. We know that the effect of this drug is in the region of RNA polymerase on TB. Unfortunately, there isn’t any three-dimensional crystal structure in the rpoß. In this study, a three-dimensional model was created from the DNA sequence and applied the resistance mutations of TB for computing resistance. There are many online tools for three-dimensional modeling using DNA or amino acid sequences. And the best result of the modeling was used in studying that’s more the same with the experimental results. After finding the best model, the mutations were applied for computing the binding energy of mutations.
Citation - WoS: 17
Citation - Scopus: 20
Identification of Potential Inhibitors of Human Methionine Aminopeptidase (type Ii) for Cancer Therapy: Structure-Based Virtual Screening, Admet Prediction and Molecular Dynamics Studies
(Elsevier, 2020) Weako, Jackson; Uba, Abdullahi Ibrahim; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Methionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.
Ekmek Mayası (saccharomyces Cerevisiae) Yardımı ile L-3,4- Dihitroksifenil Alanin (l-dopa) için Yeni Bir Sentez Yöntemi
(TUBITAK Scientific & Technical Research Council Turkey, 1997) Yelekçi, Kemal; Hamamcı, Haluk; Kahraman, M. Vezir; Karataş, Sevim
Ekmek mayası (saccharomyces cerevisiae) kolay ve ucuz bulunan bir reaktif olmasına karşın, organik kimyada yaptığı tepkimeler hem ilginç hem de diğer sentez yöntemleri ile yapılması ya imkansız ya da çok zordur. Bu amaçla klasik organik sentez yöntemleri ve maya kullanılarak daha önce sentezi bu yolla denenmeyen, anti parkinson ilacı L-3,4-Dihidroksifenilalanin'in sentezine yönelik ikisi orjinal dört önemli substurat hazırlanacak ve bu substratlar üzerinde bulunan karbon karbon çift bağı ekmek mayası ile stereospesifık olarak indirgenmeye çalışılacaktır.
Citation - WoS: 53
Citation - Scopus: 64
Synthesis of Some Novel Hydrazone and 2-Pyrazoline Derivatives: Monoamine Oxidase Inhibitory Activities and Docking Studies
(Pergamon-Elsevier Science Ltd, 2014) Evranos-Aksoz, Begum; Yabanoglu-Ciftci, Samiye; Ucar, Gulberk; Yelekçi, Kemal; Ertan, Rahmiye
A novel series of 2-pyrazoline and hydrazone derivatives were synthesized and investigated for their human monoamine oxidase (hMAO) inhibitory activity. All compounds inhibited the hMAO isoforms (MAO-A or MAO-B) competitively and reversibly. With the exception of 5i which was a selective MAO-B inhibitor all derivatives inhibited hMAO-A potently and selectively. According to the experimental K-i values compounds 6e and 6h exhibited the highest inhibitory activity towards the hMAO-A whereas compound 5j which carries a bromine atom at R-4 of the A ring of the pyrazoline appeared to be the most selective MAO-A inhibitor. Tested compounds were docked computationally into the active site of the hMAO-A and hMAO-B isozymes. The computationally obtained results were in good agreement with the corresponding experimental values. (C) 2014 Elsevier Ltd. All rights reserved.
Augmented Virtual Crossmatch for Donor-Induced Antibody Prediction by Using High Resolution Human Leukocyte Antigen Typing and Human Leukocyte Antigen Epitope Mapping for Better Donor Match
(Kadir Has Üniversitesi, 2023) Karadeniz, Sedat Tanju; Yelekçi, Kemal
The Human Leukocyte Antigen (HLA) disparity between donors and recipients is the primary driver of Donor Specific Antibodies (DSA) formation and graft rejection after transplantation. We aimed to predict the DSA by finding the HLA antigen mismatches, searching the eplets of antigens that bind to the recipient's anti-HLA antibodies, calculating the number of shared eplets between the mismatched donor HLA antigens and the recipient's pre-transplantation anti-HLA antibody-bound antigens. We have used recipient-donor HLA Typing results and the recipient's pre-transplantation and post-transplantation anti-HLA antibody detection results by Luminex single antigen bead (Luminex-SAB) assay as retrospective data for calculation in five steps. We have compared the HLA Typing results to find the mismatched antigens in the first step and searched the relevant eplets for the recipient's pre-transplantation anti-HLA antibodies in the second step. Then we calculated the shared eplets between the donor's mismatched HLA antigens and the recipient's pre-transplantation anti-HLA antibodies to find the highest number of shares, then listed the most shared anti-HLA antibodies as the most probable DSA in the fourth step. Then, we confirmed the possible epitope's peptide AA (amino acid) sequences with the IEDB Bepipred-1.0 Antibody Epitope Prediction method using the donor's HLA antigen AA sequence.
Designing Inhibitors Via Molecular Modelling Methods for Monoamine Oxidase Isozymes a and B
(Kadir Has Üniversitesi, 2012) Varnalı, Filiz; Yelekçi, Kemal
in drug development studies a large number of new drug candidates (leads)have to be synthesized and optimized by changing several moieties of the leads in order to increase efficacies and decrease toxicities. Each synthesis of these new drug candidates include multi-steps procedures. -- Abstract'dan.
Designing of Selective and Potent Inhibitors Against Histone Deacetylase Enzymes (hdac6 Ve Hdac10) Via in Silico Screening and Molecular Modeling Techniques for the Treatment of Cancer
(Kadir Has Üniversitesi, 2021) Mert, Naz Mina; Yelekçi, Kemal
HDACs are the class of enzymes that are involved in the process of cancer development by removing the acetyl groups from histone protein, inducing chromatin condensation and in this way regulating the expression of tumor suppressor genes. HDACs grouped into four classes based on their homology to their respective yeast orthologous. Class I, II and IV HDACs contain zinc as a cofactor in their active site, whereas class III HDACs are NAD+-dependent enzymes known as sirtuins. Class I, II and IV HDACs are shown to be promising anticancer targets in drug development. Especially, hydroxamic acid derivatives show significant potential for inhibiting histone deacetylases efficantly in many cancer types. But, the selectivity of these inhibitors for various HDAC isoenzymes and cancer types keeps its mystery in current researches. The overexpression of HDAC isoforms is not same in all cancer types; in which the Class I and IIb HDAC isoforms are seemed to be overexpressed in cutaneous and hematologic cancer cells on the contrary to normal organ and endothelial cells. Thence, the selective inhibition of the Class IIb HDACs became quite outstanding targets in cancer chemotherapies. Class IIb HDACs are studied in silico studies aiming to discover lead compounds that could have the potential to be a drug candidate. The X-ray crystal structure of Class IIb HDAC6 was retrieved from protein data bank (PDB) and prepared for further screening and docking processes by certain docking programs like AutoDock 4.2, AutoDockVina, and GOLD. Likewise, the crystal 3D structure of the Class IIb HDAC10 was obtained from our group's previous homology modeling studies because the X-ray crystal structure of HDAC10 has not resolved yet. By structure-based virtual screening, numerous small molecule databanks such as cancer-like compound database libraries and ZINC database, potential drug candidates against HDAC6 and HDAC10 is determined. The top inhibitors having good binding affinity and selectivity were subjected to structure-based in silico absorption, distribution, metabolism, elimination and toxicity (ADMET) prediction that show their drug-likeness properties. Moreover, molecular dynamics (MD) simulations are applied to their docking complexes to observe the stability of the ligand's binding modes. Based on this, promising novel and selective inhibitor candidates will be purchased along with the enzymes and their experimental biological activities will be tested as an anticancer drug. The compounds showing the highest inhibition activity are aimed to be used in cancer cell lines for further researches in drug discovery and drug development.
In Silico Design and Modeling of Coumarin Derivatives as Selective Monoamine Oxidase a Inhibitors
(Kadir Has Üniversitesi, 2014) Karaman, Dilara; Yelekçi, Kemal
Selective and reversible inhibition of Monoamine Oxidase (MAO) isoenzymes has an important place in treatment of various neurological disorders. Out of the two isoforms of Monoamine Oxidase enzymes inhibition of MAO-A have been giving positive results in treatment of depression and inhibition of MAO-B in cure of Parkinson’s disease. The difference in treatment is due to the fact that these two enzymes have different substrate specificities. in this study 125 different coumarin derivatives were designed by adding 5 different side groups to 3rd 5th 7th positions of coumarin nucleus. These coumarin derivatives were tested in terms of affinity to MAO enzymes by using computational methods in silico. Using to AutoDock4.2 docking software’s results we have found that most of these derivatives had affinity for both MAO-A and MAO-B enzymes at nanomolar and micromolar levels. At the same time we have seen that the coumarin derivatives had more inhibition properties with MAO-A. Binding properties of each the best five derivatives for MAO-A and MAO-B were examined comprehensively by using Accelrys Discovery Studio software. According to these results M123 ligand might be the best coumarin derivative in the 125 ligands because M123 ligand was the best second inhibitor and the most selective inhibitor. Other results from this study showed that while using phenyl as side group increased the selectivity using of phenyl and bromine increased the affinity to MAO-B but also decreased the selectivity. This study demonstrates that coumarin derivatives having particular phenyl at 7th position are effective at the MAO-A inhibition and coumarin derivatives that will be improved in this direction may be candidates in treatment of depression. -- Abstract'tan.
Design and Synthesis of Novel 2-Pyrazoline Analogues and Their Hmao Inhibitory Activities
(Wiley-Blackwell, 2015) Uçar, Gülberk; Evranos-Aksoz, Begum; Yabanoglu-Çiftçi, Samiye; Yelekçi, Kemal
[Abstract Not Available]
Citation - WoS: 23
Citation - Scopus: 26
Absolute Configuration and Biological Profile of Pyrazoline Enantiomers as Mao Inhibitory Activity
(Wiley, 2019) Goksen, Umut Salgin; Sarıgül, Sevgi; Bultinck, Patrick; Herrebout, Wouter; Doğan, İlknur; Yelekçi, Kemal; Uçar, Gülberk; Kelekçi, Nesrin Gökhan
A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (K-i = 0.85 x 10(-3) +/- 0.05 x 10(-3) mu M and SI: 2.35 x 10(-5)) whereas S was determined as poorer compound than R in terms of K-i and SI (0.184 +/- 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.
Citation - WoS: 50
Citation - Scopus: 59
A Computational Study on the Amine-Oxidation Mechanism of Monoamine Oxidase: Insight Into the Polar Nucleophilic Mechanism
(Royal Soc Chemistry, 2006) Sağ Erdem, Safiye; Karahan, Özlem; Yıldız, İbrahim; Yelekçi, Kemal
The proposed polar nucleophilic mechanism of MAO was investigated using quantum chemical calculations employing the semi-empirical PM3 method. In order to mimic the reaction at the enzyme's active site the reactions between the flavin and the p-substituted benzylamine substrate analogs were modeled. Activation energies and rate constants of all the reactions were calculated and compared with the published experimental data. The results showed that electron-withdrawing groups at the para position of benzylamine increase the reaction rate. A good correlation between the log of the calculated rate constants and the electronic parameter (sigma) of the substituent was obtained. These results agree with the previous kinetic experiments on the effect of p-substituents on the reduction of MAO-A by benzylamine analogs. In addition the calculated rate constants showed a correlation with the rate of reduction of the flavin in MAO-A. In order to verify the results obtained from the PM3 method single-point B3LYP/6-31G*//PM3 calculations were performed. These results demonstrated a strong reduction in the activation energy for the reaction of benzylamine derivatives having electron-withdrawing substituents which is in agreement with the PM3 calculations and the previous experimental QSAR study. PM3 and B3LYP/6-31G* energy surfaces were obtained for the overall reaction of benzylamine with flavin. Results suggest that PM3 is a reasonable method for studying this kind of reaction. These theoretical findings support the proposed polar nucleophilic mechanism for MAO-A.