Hsp90 Proteini için İnhibitör Olabilecek Yeni Heterosiklik Yapı İçeren Moleküllerin Sentezi ve in-silico Analizleri ile Biyo-aktivite Özelliklerinin İncelenmesi
Küçük Resim Yok
Tarih
2023
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Selçuk Üniversitesi Fen Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Kemoterapi kanser tedavisinde önemli bir rol almaktadır. Günümüzdeki moleküler biyoloji ve kanser biyokimyası alanındaki gelişmeler ile kanser oluşum mekanizmaları aydınlatılmakta ve bu mekanizmalarda görev alan hedef biyomoleküllerin tespit edilmesi ile hedefe spesifik kanser tedavisi ön plana çıkmıştır. Kemoterapiye destek olarak geliştirilen hedefe spesifik ilaç moleküllerinin tasarımı ile kemoterapinin etkinliğinin arttırılması ve hastada ortaya çıkan yan etkilerin azaltılması hedeflenmiştir. Son yıllarda Hsp protein ailesinin kanser oluşumundaki görevleri belirlenmiş olup bu proteinler hedefe spesifik kanser ilaç çalışmalarının öncül biyomolekülleri haline gelmiştir. Hsp proteinlerinin inhibisyonu için tasarlanan inhibitörler yeni kanser ilaçların keşfi için bir umut vaat etmektedir. Isı şoku protein 90 (Hsp90), 90 kDa ağırlığında, hücre içerisinde en yaygın olarak bulunan korunmuş bir şaperon proteindir ve proteinlerin doğru katlanmasında, düzenlenmesinde, stabilizasyonunda görev alır. Hücre stres koşullarının etkisindeyken özellikle kanserli hücrelerde Hsp90'nın ekspresyon düzeyi artar. Kanser hücrelerinde Hsp90, kanser metabolizması için gerekli olan onkogenik proteinlerin katlanmasında görev alır. Ayrıca apoptozu baskılar ve kanserli hücrelerin proliferasyonunu ve metastaz, anjiyogenez, invazyon ve ilaç direnci sinyal yolaklarının aktivasyonunu tetikler. Kısaca Hsp90 kanserli hücrelerin devamlılığı için gerekli bir şaperon proteindir. Hsp90 N-terminal domaininde (NTD) ökaryotik ve prokaryotik canlılarda yüksek derecede korunmuş ATP bağlanma bölgesine sahiptir. Hsp90 görevini yerine getirmek için ATP'nin hidroliz enerjisine ihtiyaç duymaktadır. Bu nedenden dolayı, Hsp90'ın ATPaz aktivitesinin inhibisyonu hedefe spesifik kanser tedavisi için önemli bir stratejidir. Bu tez çalışmasında mevcut Hsp90 inhibitörlerinden veya ATP molekülünden daha yüksek afinite ile Hsp90 N-terminal domaine bağlanan ve düşük konsantrasyonlarda dahi Hsp90'ın aktivitesini büyük oranda azaltabilecek farklı yeni inhibitörlerin tasarımı hedeflenmiştir. Bu hedef doğrultusunda tasarlayıp geliştirdiğimiz yeni aday Hsp90 inhibitörleri Hsp90'ın ATP prosesini bloke etmek için ATP'den daha yüksek bir afinite ile N-terminal domaine (NTD) bağlanıp bağlanamayacağı yapılacak in-silico analizlerle belirlendi. Elde edilen bilgisayar destekli sonuçlar doğrultusunda en iyi sonuç veren INH-1 ve HBT-Q moleküllerinin sentezleri Selçuk Üniversitesi Organik Kimya laboratuvarda gerçekleştirildi. Daha sonra bu moleküllerin biyokimyasal deneyleri Sağlık Bilimleri Üniversitesi Biyokimya laboratuvarında Prof. Dr. Yusuf TUTAR önderliğinde gerçekleştirildi.
Chemotherapy plays an important role in cancer treatment. With the recent developments in molecular biology and cancer biochemistry, the mechanisms of cancer formation are illuminated, and target-specific cancer treatment has come to the fore with the detection of target biomolecules involved in these mechanisms. With the design of target-specific drug molecules developed as a support for chemotherapy, it is aimed to increase the effectiveness of chemotherapy and to reduce the side effects that occur in the patient. In recent years, the roles of the Hsp protein family in cancer formation have been determined, and these proteins have become the precursor biomolecules of target-specific cancer drug studies. Inhibitors designed for the inhibition of Hsp proteins hold promise for the discovery of new cancer drugs. Heat shock protein 90 (Hsp90) is a 90 kDa conserved chaperone protein that is the most common in the cell and is involved in the correct folding, regulation, and stabilization of proteins. The expression level of Hsp90 increases, especially in cancer cells, when the cell is under the influence of stress conditions. In cancer cells, Hsp90 is involved in the folding of oncogenic proteins required for cancer metabolism. It also suppresses apoptosis and triggers proliferation of cancerous cells and activation of metastasis, angiogenesis, invasion, and drug resistance signaling pathways. In short, Hsp90 is an essential chaperone protein for the maintenance of cancer cells. Hsp90 has a highly conserved ATP binding site in its N-terminal domain (NTD) in eukaryotic and prokaryotic organisms. Hsp90 needs the hydrolysis energy of ATP to do its job. For this reason, inhibition of Hsp90's ATPase activity is an important strategy for target-specific cancer therapy. In this thesis, it is aimed to design different new inhibitors that bind to the Hsp90 N-terminal domain with higher affinity than existing Hsp90 inhibitors or ATP molecule and can greatly reduce the activity of Hsp90 even at low concentrations. The new candidate Hsp90 inhibitors that we designed and developed in line with this goal were determined by in-silico analyzes whether Hsp90 can bind to the N-terminal domain (NTD) with a higher affinity than ATP to block the ATP process. Synthesis of INH-1 and HBT-Q molecules, which gave the best results in line with the computer-aided results obtained, was carried out in the Organic Chemistry laboratory of Selçuk University. Then, the biochemical experiments of these molecules were carried out in the Biochemistry laboratory of the University of Health Sciences under the leadership of Prof. Dr. Yusuf TUTAR.
Chemotherapy plays an important role in cancer treatment. With the recent developments in molecular biology and cancer biochemistry, the mechanisms of cancer formation are illuminated, and target-specific cancer treatment has come to the fore with the detection of target biomolecules involved in these mechanisms. With the design of target-specific drug molecules developed as a support for chemotherapy, it is aimed to increase the effectiveness of chemotherapy and to reduce the side effects that occur in the patient. In recent years, the roles of the Hsp protein family in cancer formation have been determined, and these proteins have become the precursor biomolecules of target-specific cancer drug studies. Inhibitors designed for the inhibition of Hsp proteins hold promise for the discovery of new cancer drugs. Heat shock protein 90 (Hsp90) is a 90 kDa conserved chaperone protein that is the most common in the cell and is involved in the correct folding, regulation, and stabilization of proteins. The expression level of Hsp90 increases, especially in cancer cells, when the cell is under the influence of stress conditions. In cancer cells, Hsp90 is involved in the folding of oncogenic proteins required for cancer metabolism. It also suppresses apoptosis and triggers proliferation of cancerous cells and activation of metastasis, angiogenesis, invasion, and drug resistance signaling pathways. In short, Hsp90 is an essential chaperone protein for the maintenance of cancer cells. Hsp90 has a highly conserved ATP binding site in its N-terminal domain (NTD) in eukaryotic and prokaryotic organisms. Hsp90 needs the hydrolysis energy of ATP to do its job. For this reason, inhibition of Hsp90's ATPase activity is an important strategy for target-specific cancer therapy. In this thesis, it is aimed to design different new inhibitors that bind to the Hsp90 N-terminal domain with higher affinity than existing Hsp90 inhibitors or ATP molecule and can greatly reduce the activity of Hsp90 even at low concentrations. The new candidate Hsp90 inhibitors that we designed and developed in line with this goal were determined by in-silico analyzes whether Hsp90 can bind to the N-terminal domain (NTD) with a higher affinity than ATP to block the ATP process. Synthesis of INH-1 and HBT-Q molecules, which gave the best results in line with the computer-aided results obtained, was carried out in the Organic Chemistry laboratory of Selçuk University. Then, the biochemical experiments of these molecules were carried out in the Biochemistry laboratory of the University of Health Sciences under the leadership of Prof. Dr. Yusuf TUTAR.
Açıklama
Anahtar Kelimeler
Hsp90, Kanser, NTD, Kanser İlaçları, ATP, ATPaz Aktivitesi, İnhibitör, Cancer, Cancer Drugs, ATPase Activity
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Eser, B. N., (2023). Hsp90 Proteini için İnhibitör Olabilecek Yeni Heterosiklik Yapı İçeren Moleküllerin Sentezi ve in-silico Analizleri ile Biyo-Aktivite Özelliklerinin İncelenmesi. (Yüksek Lisans Tezi). Selçuk Üniversitesi, Fen Bilimleri Enstitüsü, Konya.
