Browsing by Author "Yelekçi, Kemal"

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Citation Count: 1
2-pirazolin yapısındaki yeni bir bileşiğin sentezi, moleküler modellemesi ve monoaminoksidaz inhibitörü etkisinin araştırılması
(2018) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, Kemal
Amaç: Nöromediatörlerin yıkımından sorumlu olanmonoamin oksidaz (MAO) enziminin izoformlarının(MAO-A ve -B) birçok hastalık ile yakından ilişkili olduğu;MAO inhibitörlerinin depresyon, Parkinson ve Alzheimerhastalığı gibi hastalıkların tedavisinde kullanıldığıbilinmektedir. Grubumuzca daha etkin, tersinir ve az yanetkili yeni bir MAO inhibitörü (SH2U bileşiği) sentezlenmişve bu bileşiğin insan MAO enzimini (hMAO) inhibe etmeyeteneği incelenmiştir. Ayrıca bu yeni bileşiğin hMAO ileetkileşimi, moleküler modelleme çalışmaları ile detaylıbir şekilde araştırılmıştır. Sentezlenen yeni bileşiğinhMAO’yu kuvvetli bir şekilde yarışmalı ve tersinir olarakinhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinsonve Alzheimer hastalıklarının tedavisinde ümit verici birilaç etken maddesi olabileceği düşünülmektedir.Yöntem: 3’,5’-Dikloro-2’-hidroksi asetofenonile p-tolualdehit’in metanol içinde KOH varlığındareaksiyona girmesiyle 1-(3,5-dikloro-2-hidroksifenil)-3-p-tolil prop-2-en-1-on (3’,5’-Dikloro-2’-hidroksi-4-metil şalkon) bileşiği sentez edilmiştir. Daha sonraelde edilen bu bileşiğin etanol içerisinde geri çevirensoğutucu altında izonikotinik asit hidrazit ile muameleedilmesiyle [3-(3,5-dikloro-2-hidroksifenil)-5-p-tolil-4,5-dihidropirazol-1-il] (piridin-4-il) metanon bileşiği sentezedilmiştir. Yapısı doğrulanan bu bileşiğin hMAO enzimi ileetkileşimi, ticari tayin kiti kullanılarak fluorometrik biryöntemle incelenmiştir. Ayrıca, söz konusu yeni bileşikile hMAO arasındaki etkileşimler, moleküler modellemeçalışmaları ile aydınlatılmıştır.Bulgular: Sentezlenen bileşiğin yapısı, IR, Mass,1H-NMR ve elemental analiz yöntemleri kullanılarakdoğrulanmıştır. Yapısı doğrulanan bu bileşiğin etkin,seçici, tersinir, toksik olmayan bir hMAO-B inhibitörüolduğu ve inhibisyonun yarışmalı olduğu görülmüştür.Moleküler yerleştirme programı kullanılarak bileşiğinhMAO-B enziminin aktif bölgesinde hangi amino asit yanzincirleri ile ne tür girişimleri yaptığı belirlenmiştir.Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-Benzimini kuvvetle, seçici, yarışmalı ve tersinir olarakinhibe etmiştir. Sentezlediğimiz bileşik, bilinen seçiciama tersinmez MAO-B inhibitörü olan selejilin’den dahaetkin ve seçici, tersinir olarak hMAO-B enzimini inhibeetmiştir ve Parkinson ile Alzheimer hastalığı tedavisindekullanılabilecek bir ilaç etken maddesi olarak ümitvadetmektedir.
Citation Count: 0
"2-pirazolin yapısındaki yeni bir bileşiğin sentezi, moleküler modellemesi ve monoaminoksidaz inhibitörü etkisinin araştırılması"
(Türkiye Halk Sağlığı Kurumu, 2018) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, Kemal
Amaç: Nöromediatörlerin yıkımından sorumlu olan monoamin oksidaz (MAO) enziminin izoformlarının (MAO-A ve -B) birçok hastalık ile yakından ilişkili olduğu; MAO inhibitörlerinin depresyon, Parkinson ve Alzheimer hastalığı gibi hastalıkların tedavisinde kullanıldığı bilinmektedir. Grubumuzca daha etkin, tersinir ve az yan etkili yeni bir MAO inhibitörü (SH2U bileşiği) sentezlenmiş ve bu bileşiğin insan MAO enzimini (hMAO) inhibe etme yeteneği incelenmiştir. Ayrıca bu yeni bileşiğin hMAO ile etkileşimi, moleküler modelleme çalışmaları ile detaylı bir şekilde araştırılmıştır. Sentezlenen yeni bileşiğin hMAO’yu kuvvetli bir şekilde yarışmalı ve tersinir olarak inhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinson ve Alzheimer hastalıklarının tedavisinde ümit verici bir ilaç etken maddesi olabileceği düşünülmektedir. Yöntem: 3’,5’-Dikloro-2’-hidroksi asetofenon ile p-tolualdehit’in metanol içinde KOH varlığında reaksiyona girmesiyle 1-(3,5-dikloro-2-hidroksifenil)- 3-p-tolil prop-2-en-1-on (3’,5’-Dikloro-2’-hidroksi-4- metil şalkon) bileşiği sentez edilmiştir. Daha sonra elde edilen bu bileşiğin etanol içerisinde geri çeviren soğutucu altında izonikotinik asit hidrazit ile muamele edilmesiyle [3-(3,5-dikloro-2-hidroksifenil)-5-p-tolil-4,5- dihidropirazol-1-il] (piridin-4-il) metanon bileşiği sentez edilmiştir. Yapısı doğrulanan bu bileşiğin hMAO enzimi ile etkileşimi, ticari tayin kiti kullanılarak fluorometrik bir yöntemle incelenmiştir. Ayrıca, söz konusu yeni bileşik ile hMAO arasındaki etkileşimler, moleküler modelleme çalışmaları ile aydınlatılmıştır. Bulgular: Sentezlenen bileşiğin yapısı, IR, Mass, 1H-NMR ve elemental analiz yöntemleri kullanılarak doğrulanmıştır. Yapısı doğrulanan bu bileşiğin etkin, seçici, tersinir, toksik olmayan bir hMAO-B inhibitörü olduğu ve inhibisyonun yarışmalı olduğu görülmüştür. Moleküler yerleştirme programı kullanılarak bileşiğin hMAO-B enziminin aktif bölgesinde hangi amino asit yan zincirleri ile ne tür girişimleri yaptığı belirlenmiştir. Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-B enzimini kuvvetle, seçici, yarışmalı ve tersinir olarak inhibe etmiştir. Sentezlediğimiz bileşik, bilinen seçici ama tersinmez MAO-B inhibitörü olan selejilin’den daha etkin ve seçici, tersinir olarak hMAO-B enzimini inhibe etmiştir ve Parkinson ile Alzheimer hastalığı tedavisinde kullanılabilecek bir ilaç etken maddesi olarak ümit vadetmektedir.
Citation Count: 18
Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity
(Wiley, 2019) Yelekçi, Kemal; 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 Count: 2
Aryl butenoic acid derivatives as a new class of histone deacetylase inhibitors: synthesis in vitro evaluation and molecular docking studies
(Scientific Technical Research Council Turkey-Tubitak, 2014) Yelekçi, Kemal; Seven, özlem; Eymur, Guluzar; Tatar, Gamze Bora; Erden, Didem Dayangaç; Yelekçi, Kemal; Yurter, Hayat; Demir, Ayhan S.
New aryl butenoic acid derivatives have been synthesized by combining hydroxy- or methoxy-substituted phenyl rings as the capping group with a double bond in the short linker as well as metal binding groups enoic ester and salts bearing either methyl or morpholine. These compounds have been shown to possess promising histone deacetylase inhibition activities via in vitro fluorometric assay and molecular docking studies.
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; 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.
Citation Count: 18
Carboxylic acid derivatives display potential selectivity for human histone deacetylase 6: Structure-based virtual screening molecular docking and dynamics simulation studies
(Elsevier Science, 2018) Yelekçi, Kemal; Yelekçi, Kemal
Human histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of alpha-tubulin making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available providing avenues for structure-based drug design campaign. Here in our continuous effort to identify potentially selective HDAC6 inhibitors structure-based virtual screening of similar to 72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated Delta G < -10 kcal/mol were manually inspected for binding mode orientation. Furthermore the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment displayed potential selectivity for HDAC6 over HDAC7 and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions and the root-mean-square deviation (RMSD) radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity. (C) 2018 Elsevier Ltd. All rights reserved.
Citation Count: 30
Cis-cyclopropylamines as mechanism-based inhibitors of monoamine oxidases
(Wiley-Blackwell, 2015) Yelekçi, Kemal; Yelekçi, Kemal; Borrello, Maria Teresa; Ganesan, A.; Semina, Elena; De Kimpe, Norbert; Mangelinckx, Sven; Ramsay, Rona R.
Cyclopropylamines inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1) provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition most compounds gave high IC50 values with MAO A but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme the inhibition was irreversible for both MAOA and MAOB and the activity was not restored by dilution. Spectral changes during inactivation of MAOA included bleaching at 456nm and an increased absorbance at 400nm consistent with flavin modification. These derivatives are MAOB-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine with an IC50 of 5nm for MAOB and 170nm for MAOA after 30min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine so may be studied as a lead for selective inhibitors of MAOB that do not inhibit LSD1.
Citation Count: 0
COMP 297-Experimental and molecular docking simulation studies of Histone deacetylases (HDACs) enzyme inhibitors
(Amer Chemical Soc, 2007) Yelekçi, Kemal; Bora, Gamze; Dayangaç-Erden, Didem; Ayhan, Peruze; Dalkara, Sevim; Demir, Ayhan S.; Erdem-Yurter, Hayat
[Abstract Not Available]
Citation Count: 4
Computational Chemistry and Molecular Modeling of Reversible MAO Inhibitors
(Humana Press Inc., 2023) Yelekçi, Kemal; Erdem, S.S.
Proper elucidation of drug-target interaction is one of the most significant steps at the early stages of the drug development research. Computer-aided drug design tools have substantial contribution to this stage. In this chapter, we specifically concentrate on the computational methods widely used to develop reversible inhibitors for monoamine oxidase (MAO) isozymes. In this context, current computational techniques in identifying the best drug candidates showing high potency are discussed. The protocols of structure-based drug design methodologies, namely, molecular docking, in silico screening, and molecular dynamics simulations, are presented. Employing case studies of safinamide binding to MAO B, we demonstrate how to use AutoDock 4.2.6 and NAMD software packages. © 2023, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
Citation Count: 48
A computational study on the amine-oxidation mechanism of monoamine oxidase: Insight into the polar nucleophilic mechanism
(Royal Soc Chemistry, 2006) Yelekçi, Kemal; 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.
Citation Count: 2
Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software
(Elsevier Science Inc, 2017) Yelekçi, Kemal; Akgül, Sebahat Usta; Öğret, Yeliz; Çiftçi, Hayriye Şentürk; Bayraktar, Adem; Bakkaloğlu, Hüseyin; Çalışkan, Yaşar Kerem; Yelekçi, Kemal; Türkmen, Aydin; Aydın, Ali Emin; Oğuz, Fatma Savran; Çarin, Mahmut Nezih; Aydın, Filiz
however the rate was 86.2% using the cPRA. Discussion. cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. Conclusion. In principal implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match particularly for hypersensitized patients by the creation of an unacceptable mismatch program using cPRA software.
Corrected PRA positivity rates for hypersensitized patients in Turkish population with calculated PRA-cPRA software
(Kadir Has Üniversitesi, 2017) Yelekçi, Kemal; Yelekçi, Kemal
Yüksek PRA (Panel Reaktif Antikor) oranları, böbrek nakli şansını düşürebilir ve nakilden önce uzun süre beklemeye yol açabilir. cPRA (Hesaplamalı Panel Reaktif Antikor), kabul edilemez (uyumsuz) HLA (Human Lökosit Antijen) antijenleri temel alınarak yapılır. Bu antijenler, serumda dolaşan HLA antijenlerine karşı gelişen antikorlara ve bu antikorların antijenlere bağlanma riskine dayanılarak oluşturulmuş bir bilgisayar programı ile tanımlanır. Böylece popülasyonun antijen profili ve antijen frekansları ölçülebilir ve bu yöntem kullanılarak daha gerçekçi cPRA pozitiflik oranları elde edilebilir. Türkiye'de EFI (European Federation Immunogenetics) tarafından akredite edilmiş iki doku tipleme laboratuvarında 494 kan bağışçısının HLA antijenlerine dayanan bir bilgisayar programı geliştirdik. Verici örneklerinin doku tiplemesi YND (Yeni Nesil Dizileme) tabanlı olarak yapıldı. İstanbul Tıp Fakültesi'nde kadavradan organ nakli yapılmasını bekleyen 380 hastaya PRA tarama testi uygulandı. 48 aşırı duyarlı hastaya antikor profillerini belirlemek için (TAT) Tek Antijen Tanımlama testi yapıldı. Duyarlılaşmış hastaların mevcut yöntemlerle PRA pozitifliği ortalama %44,6, ancak cPRA yazılımı kullanılarak pozitifliği ortalama %86,2 bulundu. cPRA yazılımı kabul edilemez tüm antijenlere göre reddedilen vericilerin oranını göstermektedir. PRA pozitiflik oranının yerine, kabul edilemez antijenlerin listesi olarak sunulan duyarlılığa bağlı hesaplamalı cPRA pozitiflik oranı ihtiyaç duyulan gerçek bir değişimdir. Esas olarak, cPRA'nın uygulanması Türkiye'de birçok merkezi ve laboratuvarı, duyarlılığın standart bir ölçümü olarak benimsemeye teşvik edecektir. cPRA yazılımını kullanmak, kabul edilemez uyuşmazlık programı oluşturarak, özellikle aşırı duyarlı hastalar için daha iyi bağış yapma şansını artıracaktır.
Citation Count: 14
Crystallographic structure versus homology model: a case study of molecular dynamics simulation of human and zebrafish histone deacetylase 10
(Taylor & Francis, 2020) Yelekçi, Kemal; 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 Count: 0
Design and synthesis of novel 2-pyrazoline analogues and their hMAO inhibitory activities
(Wiley-Blackwell, 2015) Yelekçi, Kemal; Evranos-Aksoz, Begum; Yabanoglu-Çiftçi, Samiye; Yelekçi, Kemal
[Abstract Not Available]
Design of novel and potent inhibitors for mPGES-1 enzyme via in silico screening
(Kadir Has Üniversitesi, 2021) Yelekçi, Kemal; Çiftçi, Gamze; Yelekçi, Kemal
To prevent inflammation in the body, non-steroidal anti-inflammatory drugs act by suppressing PGE2 production as a result of non-selective inhibition of both COX-1 and COX-2 enzymes. As a result of the inhibition of COX-1 and COX-2, gastrointestinal poisoning and cardiovascular complications occurred, respectively. mPGES-1 inhibitors have been shown to have no known side effects. Thus, inhibition of PGE2 biosynthesis by inhibition of mPGES-1 has become a new therapeutic target in the treatment of inflammatory diseases, which is considered to be clinically safer. In this thesis, approximately 2.5 million ligands were downloaded from the ZINC particle library to screen the mPGES-1 enzyme. Prescreening of these ligands was performed with Autodock-Vina. 1261 compounds were scanned using Autodock 4. Binding energies and poses were determined. Based on the known inhibitor study available on the market. The best inhibitors were subjected to the ADMET test, and molecular dynamic simulation was performed for the four inhibitors determined as the best according to this test, and RMSD, RMSF, and Rg values were analyzed.
Citation Count: 6
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) Yelekçi, Kemal; 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 Count: 5
Design, Synthesis and hMAO Inhibitory Screening of Novel 2-Pyrazoline Analogues
(Bentham Science Publ Ltd, 2017) Yelekçi, Kemal; Uçar, Gülberk; Yelekçi, Kemal
Aim and Objective: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates. Materials and Methods: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells. Results: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004 +/- 0.001 and 0.005 +/- 0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10(-5) and 0.003, respectively). Both of these compounds were found non toxic at 1 mu M, 5 mu M and 25 mu M concentrations. Conclusion: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)- 4,5-dihydropyrazol-1-yl)(phenyl) methanone and (3-(2-hydroxy-4-methoxy phenyl)5- p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.
Citation Count: 0
Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper(I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs
(Frontiers Media Sa, 2022) Yelekçi, Kemal; Peng, Wenjing; Unruh, Daniel; Mayer, Michael F.; Mechref, Yehia; Yelekci, Kemal
Breast cancer is the second type of cancer with a high probability of brain metastasis and has always been one of the main problems of breast cancer research due to the lack of effective treatment methods. Demand for developing an effective drug against breast cancer brain metastasis and finding molecular mechanisms that play a role in effective treatment are gradually increasing. However, there is no effective anticancer therapeutic drug or treatment method specific to breast cancer, in particular, for patients with a high risk of brain metastases. It is known that mTOR and HDAC enzymes play essential roles in the development of breast cancer brain metastasis. Therefore, it is vital to develop some new drugs and conduct studies toward the inhibition of these enzymes that might be a possible solution to treat breast cancer brain metastasis. In this study, a series of 1,10-phenanthroline and Prodigiosin derivatives consisting of their copper(I) complexes have been synthesized and characterized. Their biological activities were tested in vitro on six different cell lines (including the normal cell line). To obtain additional parallel validations of the experimental data, some in silico modeling studies were carried out with mTOR and HDAC1 enzymes, which are very crucial drug targets, to discover novel and potent drugs for breast cancer and related brain metastases disease.
Designing inhibitors via molecular modelling methods for monoamine oxidase isozymes a and b
(Kadir Has Üniversitesi, 2012) Yelekçi, Kemal; 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) Yelekçi, Kemal; 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.