Browsing by Author "Yelekçi, K."

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    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.
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    Article
    Citation Count: 1
    Investigation of synthesis, molecular modelling and monoaminoxidase inhibitor activity of a new 2-pyrazoline compound
    (Refik Saydam National Public Health Agency (RSNPHA), 2018) Yelekçi, Kemal; Uçar, G.; Yelekçi, K.
    Objective: Isoforms of monoamine oxidase (MAO-A and -B) which are responsible for the degradation of neuromediators are involved in many diseases, and MAO inhibitors are used for the treatment of some diseases such as depression, Alzheimer's and Parkinson's diseases. Thus, a novel compound, SH2U was synthesized and its ability for the inhibition of human MAO (hMAO) activity was investigated by our group. In addition, the interaction of SH2U with hMAO isoforms have been investigated in detail using molecular modelling technics. It has been found that SH2U inhibited hMAO-B potently, selectively, competitively and reversibly suggesting that the novel compound may be a promising drug agent for the treatment of Parkinson's and Alzheimer's diseases. Methods: 1-(3,5-dichloro-2-hydroxyphenyl)-3- p-tolylprop-2-ene-1-on (3',5'-Dichloro-2'-hydroxy- 4-methyl chalcone) was prepared via the reaction of p-tolualdehyde and 3',5'-Dichloro-2'-hydroxy acetophenone in methanol in the presence of KOH. Then, the obtained chalcone was treated with isonicotinic acid hydrazide under reflux in ethanol to give (3-(3,5-Dichloro-2-hydroxy phenyl)-5-p-tolyl- 4,5-dihydropyrazol-1-yl) (pyridin-4-yl) methanone. The interaction of SH2U with hMAO isoforms was investigated fluorometrically using commercial kits. The interaction between SH2U and hMAO was also analyzed using AutoDock 4.2.6 program. Results: The structure of compound SH2U was confirmed using IR, Mass, 1 H-NMR and elemental analysis methods. SH2U appeared as a potent, selective, reversible and nontoxic hMAO-B inhibitor. Mode of inhibition was found to be competitive. Interactions of the new compound with the active site of hMAO-B were clarified using molecular modelling studies. Conclusion: Compound SH2U inhibited hMAO-B potently, selectively, competitively and reversibly. The synthesized compound is found to be more potent and selective than selegiline, the known irreversible MAO-B inhibitor, indicating that SH2U appears as a promising active molecule to be used in the treatment of Parkinson's and Alzheimer's diseases. © 2018 Refik Saydam National Public Health Agency (RSNPHA).Amaç: Nöromediatörlerin yikimindan sorumlu olan monoamin oksidaz (MAO) enziminin izoformlarinin (MAO-A ve -B) birçok hastalik ile yakindan ilişkili olduğu; MAO inhibitörlerinin depresyon, Parkinson ve Alzheimer hastaliği gibi hastaliklarin tedavisinde kullanildigi 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. Ayrica bu yeni bileşiğin hMAO ile etkileşimi, moleküler modelleme çalişmalari ile detayli bir şekilde araştirilmiştir. Sentezlenen yeni bileşiğin hMAO'yu kuvvetli bir şekilde yarişmali ve tersinir olarak inhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinson ve Alzheimer hastaliklarinin tedavisinde ümit verici bir ilaç etken maddesi olabileceği düşünülmektedir. Yöntem: 3',5'-Dikloro-2'-hidroksi asetofenon ile p-tolualdehit'in metanol içinde KOH varliginda 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 sogutucu altinda 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. Yapisi doğrulanan bu bileşiğin hMAO enzimi ile etkileşimi, ticari tayin kiti kullanilarak fluorometrik bir yöntemle incelenmiştir. Ayrica, söz konusu yeni bileşik ile hMAO arasindaki etkileşimler, moleküler modelleme çalişmalari ile aydinlatilmiştir. Bulgular: Sentezlenen bileşiğin yapisi, IR, Mass, 1H-NMR ve elemental analiz yöntemleri kullanilarak doğrulanmiştir. Yapisi doğrulanan bu bilesigin etkin, seçici, tersinir, toksik olmayan bir hMAO-B inhibitörü olduğu ve inhibisyonun yarişmali olduğu görülmüştür. Moleküler yerleştirme programi kullanilarak bileşiğin hMAO-B enziminin aktif bölgesinde hangi amino asit yan zincirleri ile ne tür girişimleri yaptiği belirlenmiştir. Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-B enzimini kuvvetle, seçici, yarişmali ve tersinir olarak inhibe etmistir. Sentezledigimiz bilesik, 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 hastaliği tedavisinde kullanilabilecek bir ilaç etken maddesi olarak ümit vadetmektedir. © 2018 Refik Saydam National Public Health Agency (RSNPHA).
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    Article
    Citation Count: 4
    Molecular modeling studies of some phytoligands from Ficus sycomorus fraction as potential inhibitors of cytochrome CYP6P3 enzyme of Anopheles coluzzii
    (University of Jordan,Deanship of Scientific Research, 2022) Yelekçi, Kemal; Anosike, C.A.; Ezeanyika, L.U.S.; Yelekçi, K.; Uba, A.I.
    The major obstacle in controlling malaria is the mosquito’s resistance to insecticides, including pyrethroids. The resistance is mainly due to the over-expression of detoxification enzymes such as cytochromes. Insecticides tolerance can be reduced by inhibitors of P450s involved in insecticide detoxification. Here, to design potential CYP6P3 inhibitors, a homology model of the enzyme was constructed using the crystal structure of retinoic acid-bound cyanobacterial CYP120A1 (PDB ID: 2VE3; Resolution: 2.1 Å). Molecular docking study and computational modeling were employed to determine the inhibitory potentials of some phytoligands isolated from Ficus sycomorus against Anopheles coluzzii modeled P450 isoforms, CYP6P3, implicated in resistance. Potential ligand optimization (LE) properties were analyzed using standard mathematical models. Compounds 5, 8,and 9 bound to the Heme iron of CYP6P3 within 3.14, 2.47 and 2.59 Å, respectively. Their respective binding energies were estimated to be-8.93,-10.44, and-12.56 Kcal/mol. To examine the stability of their binding mode, the resulting docking complexes of these compounds with CYP6P3 were subjected to 50 ns MD simulation. The compounds remained bound to the enzyme and Fe (Heme):O (Ligand) distance appeared to be maintained over time. The coordination of a strong ligand to the heme iron shifts the iron from the high-to the stable low-spin form and prevented oxygen from binding to the heme thereby inhibiting the catalytic activity. The LE index showed the high potential of these compounds (5 and 8) to provide a core fragment for optimization into potent P450 inhibitors. © 2022 DSR Publishers/The University of Jordan. All Rights Reserved.
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    Article
    Citation Count: 0
    Novel azole-urea hybrids as VEGFR-2 inhibitors: Synthesis, in vitro antiproliferative evaluation and in silico studies
    (Elsevier B.V., 2023) Yelekçi, Kemal; Kulabaş, N.; Erdoğan, Ö.; Çevik, Ö.; Dere, D.; Yelekçi, K.; Danış, Ö.
    The vascular endothelial growth factor receptor-2 (VEGFR-2) is a receptor tyrosine kinase known to be abnormally expressed in various malignant tumors, including breast cancer, and is considered one of the most important contributors to tumor angiogenesis. Sorafenib is one of many VEGFR-2 inhibitors that have received approval for clinical use from the US FDA in recent years. Accordingly, in this study, the synthesis of two new pyrazoles, six 1,3,4-oxadiazoles, four 1,3,4-thiadiazoles, and ten 1,2,4-triazole-3-thione derivatives having structural characteristics similar to sorafenib was carried out. A preliminary screening of synthesized compounds and known inhibitors sorafenib and staurosporine at 10 µM concentration on in vitro activity of VEGFR-2 was performed, and compounds 10c, 8a, and 11 g were identified as the most potent derivatives with% VEGFR-2 residual activities lower than 30%, and dose-dependent inhibition studies was carried out to determine the IC50 values of these inhibitors. Compound 10c was found to be the most potent inhibitor of VEGFR-2 activity with an IC50 value of 0.664 µM. The anti-proliferative activity of synthesized derivatives was assessed against a breast carcinoma (MCF-7) cell line, a triple negative human breast adenocarcinoma (MDA-MB-231) cell line, and noncancerous fibroblast cells (L929). Compound 8a displayed superior activity when compared to sorafenib against MCF-7 (7.69 fold) and MDA-MB-231 (1.52 fold) cell lines while displaying 3.75-fold less toxicity against the normal L929 cell line. Annexin V binding assay revealed that compound 8a significantly increased early and late apoptosis in MCF-7 cells and late apoptosis and necrosis in MDA-MB-231 cells. Computational studies such as molecular docking and ADMET evaluation were performed to elucidate the binding interactions and drug-likeness of the synthesized compounds. The results indicate that compound 8a could be a promising candidate for the development of a novel anti-angiogenic and anti-proliferative agent. © 2023