In silico design and modeling of peptidomimetic drug candidates for methionine aminopeptidase 2 enzyme for prevention of cancer
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Date
2019
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Kadir Has Üniversitesi
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Abstract
Birçok hastalık bir araya gelerek kanseri oluşturur. Kanser hücreleri kontrolsüz bir şekilde bölünür. Kanserde hücre çoğalması anormaldir. Yıllar içinde 200'den fazla kanser çeşidi teşhis edilmiştir. Bazı faktörler kansere neden olabilir. Kalıtım, beslenme, hormonlar, sigara içme, alkol tüketimi, radyasyon, bazı kimyasallar, virüsler ve bakteriler bu faktörlerden birkaçıdır. 2018 yılında 17 milyon yeni kanser vakası ve 9.5 milyon kanser nedenli ölüm gözlenmiştir. Metiyonin aminopeptidaz (MetAP 2) kobalt içeren ve hücrenin sitozolünde bulunan bir metalloproteazdır. Bu enzim yeni sentezlenmiş proteinin amino kısmında bulunan metiyonin amino asidini proteinden ayırır. Ayrıca kanser tedavisinde anjiyojenezi önlemek için yeni peptidomimetik inhibitörler keşfedilmesinde bu enzim kullanılır. Peptidomimetikler peptitlerin işlev ve yapısını taklit etmek için dizayn edilir. Peptitlere göre peptidomimetikler daha yüksek biyoyararlılık ve daha az yan etki gösterir. Bu çalışmada, Discovery Studio adlı program kullanılarak peptidomimetik inhibitörler dizayn edilmiştir. Daha sonra hedef reseptör (MetAP 2) ve inhibitörler birbirlerine bağlanarak en iyi bağlanma modları bulunmuştur. Son olarak Gibbs serbest enerjisi ve ADMET özelliklerine bakılarak en iyi 10 peptidomimetik inhibitör seçilmiştir. MetAP 2 enzimine karşı dizayn edilen bu peptidomimetik inhibitörler yakın gelecekte ilaç dizaynında umut verici işler başaracaktır.
Several disorders come together to form cancer. Cancer cells divide without a control. The cell proliferation in cancer is abnormal. More than 200 types of cancer have been diagnosed over the years. There are various factors that can cause cancer. These factors are heredity, diet, hormones, smoking, alcohol, viruses, bacteria, radiation and some chemicals. 17 million new cancer cases and 9.5 million cancer deaths were observed in 2018. Methionine Aminopeptidase 2 (MetAP 2) is a cobalt-containing metalloprotease located in cytosol of the cell. It cleaves methionine from amino terminus of a newly synthesized protein. MetAP 2 is a target for discovering new peptidomimetic inhibitors for angiogenesis used as an effective treatment for cancer. Peptidomimetics are designed to mimic peptide function and structure. They show high bioavailability and less side effects than peptides. Here, in this study we designed several peptidomimetic inhibitors using Discovery Studio. We used molecular docking to find best-fit modes between inhibitors and the target, MetAP 2. Lastly, 10 possible peptidomimetic inhibitors were obtained by further analysis such as Gibbs Free Energy and ADMET properties. These peptidomimetic inhibitors will serve as a promising drug candidates for MetAP 2 enzyme in drug design and development in the near future.
Several disorders come together to form cancer. Cancer cells divide without a control. The cell proliferation in cancer is abnormal. More than 200 types of cancer have been diagnosed over the years. There are various factors that can cause cancer. These factors are heredity, diet, hormones, smoking, alcohol, viruses, bacteria, radiation and some chemicals. 17 million new cancer cases and 9.5 million cancer deaths were observed in 2018. Methionine Aminopeptidase 2 (MetAP 2) is a cobalt-containing metalloprotease located in cytosol of the cell. It cleaves methionine from amino terminus of a newly synthesized protein. MetAP 2 is a target for discovering new peptidomimetic inhibitors for angiogenesis used as an effective treatment for cancer. Peptidomimetics are designed to mimic peptide function and structure. They show high bioavailability and less side effects than peptides. Here, in this study we designed several peptidomimetic inhibitors using Discovery Studio. We used molecular docking to find best-fit modes between inhibitors and the target, MetAP 2. Lastly, 10 possible peptidomimetic inhibitors were obtained by further analysis such as Gibbs Free Energy and ADMET properties. These peptidomimetic inhibitors will serve as a promising drug candidates for MetAP 2 enzyme in drug design and development in the near future.
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Biyoloji, Biology