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

Mehmet Özcan; Müjgan Ercan

Article Details

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

Authors:

Mehmet Özcan | Müjgan Ercan

Publisher:

Yozgat Bozok University

Main Topics:

Tıbbi biyokimya - Proteinler | Peptitler ve Proteomik

Journal:

Bozok Tıp Dergisi Vol.15 Issue 2, pp.178-185

Document Type:

Article

Publication Date:

6/2025

Document Language:

English

Document ID (Org No.):

2001350373

pISSN:

2146-4006

Keywords:

Abstract:

 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 kcalmol, surpassing ethacrynic acid -6.7 kcalmol. Vadimezan -7.9 kcalmol and SLC-0111 -7.2 kcalmol 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 kcalmol. 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.

 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 kcalmol, surpassing ethacrynic acid -6.7 kcalmol. Vadimezan -7.9 kcalmol and SLC-0111 -7.2 kcalmol 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 kcalmol. 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.

 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 kcalmol, surpassing ethacrynic acid -6.7 kcalmol. Vadimezan -7.9 kcalmol and SLC-0111 -7.2 kcalmol 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 kcalmol. 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.

 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, GSTP1in 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 kcalmol bağlanma enerjisi ile GSTP1e en yüksek bağlanma afinitesini gösterdi ve etakrinik asiti -6.7 kcalmol geride bıraktı. Vadimezan -7.9 kcalmol ve SLC-0111 -7.2 kcalmol 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 kcalmol 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.

Article Details

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

Authors:

Mehmet Özcan | Müjgan Ercan

Publisher:

Yozgat Bozok University

Main Topics:

Tıbbi biyokimya - Proteinler | Peptitler ve Proteomik

Journal:

Bozok Tıp Dergisi Vol.15 Issue 2, pp.178-185

Document Type:

Article

Publication Date:

6/2025

Document Language:

English

Document ID (Org No.):

2001350373

pISSN:

2146-4006

Hypoxia

GSTP1

Drug resistance

Molecular dockingHipoksi

GSTP1

İlaç direnci

Moleküler yerleştirme

Issues

Article Details

Authors: Mehmet Özcan | Müjgan Ercan

Publisher: Yozgat Bozok University

Main Topics: Tıbbi biyokimya - Proteinler | Peptitler ve Proteomik

Journal: Bozok Tıp Dergisi Vol.15 Issue 2, pp.178-185

Document Type: Article

Publication Date: 6/2025

Document Language: English

Document ID (Org No.): 2001350373

pISSN: 2146-4006

Issues

Authors:

Mehmet Özcan | Müjgan Ercan

Publisher:

Yozgat Bozok University

Main Topics:

Tıbbi biyokimya - Proteinler | Peptitler ve Proteomik

Journal:

Bozok Tıp Dergisi Vol.15 Issue 2, pp.178-185

Document Type:

Article

Publication Date:

6/2025

Document Language:

English

Document ID (Org No.):

2001350373

pISSN:

2146-4006