ASSESSING THE POTENTIAL OF HYPOXIA-TARGETING AGENTS AS GSTP1 INHIBITORS IN OVERCOMING CANCER DRUG RESISTANCE

Öz

Objective: The persistent challenge of drug resistance in cancer therapy is closely linked to the detoxification activity of glutathione S-transferase pi (GSTP1). This study aims to assess the potential of hypoxia-targeting agents as GSTP1 inhibitors to address drug resistance mechanisms in cancer. Materials and Methods: Molecular docking simulations were performed using the crystal structure of GSTP1 (PDB ID: 2GSS). Eight hypoxia-targeting agents were tested, including BAY 87-2243, Vadimezan, SLC-0111, Acriflavine, PX-478, Evofosfamide, Bevacizumab, and the reference GSTP1 inhibitor ethacrynic acid. Binding affinities were calculated using AutoDock Vina, and interaction profiles were visualized with Discovery Studio. Results: Among the tested compounds, BAY 87-2243 exhibited the highest binding affinity to GSTP1 with a binding energy of -9.1 kcal/mol, surpassing ethacrynic acid (-6.7 kcal/mol). Vadimezan (-7.9 kcal/mol) and SLC-0111 (-7.2 kcal/mol) also demonstrated strong inhibitory potential. Key interactions included hydrogen bonds with residues GLN A:51 and ARG A:13 and hydrophobic interactions with PHE A:8. Other compounds displayed lower binding affinities, ranging from -6.6 to -5.7 kcal/mol. Conclusion: Hypoxia-targeting agents, particularly BAY 87-2243, Vadimezan, and SLC-0111, show promising GSTP1 inhibition potential, offering dual functionality to modulate tumor hypoxia and counteract drug resistance. These findings warrant further in vitro and in vivo studies to explore their clinical application in cancer therapy.

Anahtar Kelimeler

• Hypoxia
• GSTP1
• Drug resistance
• Molecular docking

Kanser İlaç Direncini Aşmada Hipoksi Hedefli Ajanların GSTP1 İnhibitörleri Olarak Potansiyellerinin Değerlendirilmesi

Öz

Amaç: Kanser tedavisinde ilaç direncinin kalıcı zorluğu, glutatyon S-transferaz pi (GSTP1) enziminin detoksifikasyon aktivitesi ile yakından ilişkilidir. Bu çalışma, kanser tedavisinde ilaç direnci mekanizmalarını hedeflemek amacıyla hipoksi odaklı ajanların GSTP1 inhibitörleri olarak potansiyelini değerlendirmeyi amaçlamaktadır. Materyal ve Yöntemler: Moleküler yerleştirme simülasyonları, GSTP1'in kristal yapısı (PDB ID: 2GSS) kullanılarak gerçekleştirildi. BAY 87-2243, Vadimezan, SLC-0111, Akflavin, PX-478, Evofosfamid, Bevacizumab ve referans GSTP1 inhibitörü olan etakrinik asit dahil olmak üzere sekiz hipoksi odaklı ajan test edildi. Bağlanma afiniteleri AutoDock Vina kullanılarak hesaplandı ve etkileşim profilleri Discovery Studio ile görselleştirildi. Bulgular: Test edilen bileşikler arasında BAY 87-2243, -9.1 kcal/mol bağlanma enerjisi ile GSTP1'e en yüksek bağlanma afinitesini gösterdi ve etakrinik asiti (-6.7 kcal/mol) geride bıraktı. Vadimezan (-7.9 kcal/mol) ve SLC-0111 (-7.2 kcal/mol) de güçlü inhibitör potansiyeli sergiledi. Önemli etkileşimler arasında GLN A:51 ve ARG A:13 kalıntıları ile hidrojen bağları ve PHE A:8 ile hidrofobik etkileşimler yer aldı. Diğer bileşikler, -6.6 ile -5.7 kcal/mol arasında değişen daha düşük bağlanma afiniteleri gösterdi. Sonuç: Hipoksi odaklı ajanlar, özellikle BAY 87-2243, Vadimezan ve SLC-0111, GSTP1 inhibisyon potansiyeli göstererek tümör hipoksisini modüle etme ve ilaç direncini azaltmada çift işlevli bir yaklaşım sunmaktadır. Bu bulgular, kanser tedavisinde klinik uygulamalarını keşfetmek için ileri in vitro ve in vivo çalışmaların yapılmasını gerektirmektedir.

Anahtar Kelimeler

• Hipoksi
• GSTP1
• İlaç direnci
• Moleküler yerleştirme

Kaynakça

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