SÜLFONAMİDOBENZOTİYAZOL TÜREVİ hGSTP1-1 İNHİBİTÖRLERİNİN TASARIMI

Year 2020, , 388 - 396, 30.09.2020

Kayhan Bolelli

https://doi.org/10.33483/jfpau.748521

Abstract

Amaç: Glutatyon Transferazlar (GST), ekzojen ve endojen kaynaklı, elektrofilik ve hidrofobik bileşiklerin GSH ile konjugasyonunu katalizleyen Faz-II detoksifikasyon enzim ailesidir. GST izozimlerinden en önemlisi olan hGSTP1-1’in çok farklı insan kaynaklı tümörde fazla miktarda salgılandığı ve kanser tedavisinde çoklu ilaç direnç (MDR) gelişimine sebep olduğu bilinmektedir. Tüm bu nedenlerden dolayı son zamanlarda hGSTP1-1 enzimi kanser tedavisi için bir hedef haline gelmiştir. Bu çalışmanın amacı yeni hGSTP1-1 inhibitörleri tasarlamaktır. 

Gereç ve Yöntem: 5F-203 bileşiğinden hareketle, önilaç şeklinde etki gösterebileceği düşünülen bir seri sülfonamidobenzotiyazol türevi bileşik tasarlanmıştır. Bu bileşiklerin hGSTP1-1 enzimi ile etkileşimlerini incelemek üzere Schrodinger Maestro programı kullanılarak moleküler doking çalışmaları yapılmıştır.

Sonuç ve Tartışma: Bu çalışmada 5F-203 bileşiğinden hareketle, önilaç şeklinde etki gösterebileceği düşünülen bileşiklerin, GST enzimi aracılığıyla metabolizasyonu sırasında gerçekleşen hidrolizle 5F-203 ve türevi bileşikler açığa çıkararak antitümör özellik gösterebilecekleri düşünülmüştür. Tasarlanan bileşiklerin hGSTP1-1 enzimi ile etkileşimlerini incelemek üzere yapılan doking çalışmalarına göre bileşiklerin tamamının hGSTP1-1 enzimi ile kuvvetli etkileşimlerinin olduğu gözlenmiştir. Bileşiklerin tamamının hGSTP1-1 enzim inhibisyonu için önemli olan Arg13 ve Tyr7 ile hidrojen bağı ve Tyr108 ile pi-pi etkileşimleri gösterdiği belirlenmiştir. Bir sonraki basamak olarak bu bileşiklerin sentezi gerçekleştirilecek ve hGSTP1-1 enzimi üzerindeki etkileri deneysel olarak test edilecektir. Böylece yapı-etki ilişkileri tanımlanarak daha etkili yeni bileşiklerin tasarlanması ve böylece direnç mekanizması inhibe edilerek antikanser ilaçların etkinliğinin artırılması söz konusu olabilecektir.

Keywords

antikanser, doking, hGSTP1-1, ilaç direnci, sülfonamidobenzotiyazol

Supporting Institution

Ankara Üniversitesi Bilimsel Araştırma Projeleri

Project Number

18H0237002

Thanks

Bu çalışma, Ankara Üniversitesi Bilimsel Araştırma Projeleri (Proje No: 18H0237002) tarafından desteklenmiştir.

DESIGN OF SULFONAMIDOBENZOTHIAZOLE DERIVATIVES AS hGSTP1-1 INHIBITORS

Abstract

Objective: The glutathione transferases (GSTs) are a family of widely distributed Phase II detoxification enzymes that catalyse the conjugation of exogenius and endogenius electrophilic and hydrophobic compounds. GSTP1-1 is frequently overexpressed in rat and human tumours. It is suggested that overexpression of hGSTP1-1 by human tumor cells may play a role in multi drug resistance (MDR) to cancer chemotherapy. Hence, hGSTP1-1 can be a promising target for cancer treatment. The aim of this study is to design new hGSTP1-1 inhibitors.

Material and Method: a series of sulfonamidobenzothiazole derivatives which are thought to act as prodrug have been designed based on the 5F-203 compound. To examine the interactions of these compounds with the hGSTP1-1 enzyme, molecular docking studies were carried out, by using the Schrodinger Maestro Software.

Result and Discussion: In this study, considering the compound 5F-203, it is thought that the compounds thought to be effective in the form of prodrugs may exhibit antitumor properties by releasing 5F-203 and its derivative compounds by hydrolysis during metabolism by GST enzyme. It has been observed that all of the compounds have strong interactions with the enzyme hGSTP1-1, according to the doking studies conducted to examine the interactions of the designed compounds with the enzyme hGSTP1-1. It was determined that all of the compounds showed hydrogen bonding with Arg13 and Tyr7, which are important for hGSTP1-1 enzyme inhibition, and pi-pi interactions with Tyr108. As a next step, the synthesis of these compounds will be carried out and their effects on the enzyme hGSTP1-1 will be tested experimentally. Thus, by defining structure-activity relationships, it can be possible to design more effective new compounds and increase the effectiveness of anticancer drugs by inhibiting the resistance mechanism.

Keywords

anticancer, docking, drug resistance, hGSTP1-1, sulfonamidobenzothiazole

Project Number

18H0237002

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