BAZI ANTİVİRAL AJANLARIN İNSAN TELOMERAZ ENZİMİ ÜZERİNDEKİ İNHİBİTÖR POTANSİYELİNİN MOLEKÜLER KENETLENME VE MOLEKÜLER DİNAMİK SİMÜLASYON ÇALIŞMALARI İLE ARAŞTIRILMASI

Year 2024, Volume: 48 Issue: 2, 576 - 585, 20.05.2024

Dilan Konyar , Muhammed Tılahun Muhammed

https://doi.org/10.33483/jfpau.1444259

Abstract

Amaç: Bu çalışmada, nükleozid ve non-nükleozid ters transkriptaz inhibitörü ilaçların, antikanser etki potansiyeli hesaplamalı yaklaşımlar kullanılarak araştırılmıştır. Bu amaçla, bu ilaçların telomeraz ters transkirptaz (TERT)'ın telomeraz temel N-terminal (TEN) alanına bağlanma potansiyeli araştırılmıştır. İlaçların TEN alanına bağlanma potansiyeli için moleküler yerleştirme çalışması yapılmıştır. Moleküler yerleştirme sonucu elde edilen protein-ilaç kompleksinin kararlılığı moleküler dinamik (MD) simülasyonu ile değerlendirilmiştir.
Gereç ve Yöntem: TERT'in TEN alanı kristal yapısı için Protein Veri Bankası (PDB) kullanılmıştır. 2,2 Å çözünürlüğe sahip PDB kodu 2B2A kristal yapı kullanımıştır. Moleküler yerleştirme çalışması için AutoDock Vina programı kullanılmıştır. Kompleksler Biovia Discovery Studio kullanılarak görselleştirilmiştir. MD simülasyonu GROMACS 2020 kullanılarak gerçekleştirilmiştir. Hem kompleksler hem de serbest protein üzerinde 200 ns boyunca bir MD simülasyonu gerçekleştirilmiştir. Omurga protein ve moleküllerin, omurga yapısına göre RMSD (kök ortalama kare sapması), RMSF (kök ortalama kare dalgalanması) ve Rg (dönme yarıçapı), Qt Grace ile gösterilmiştir.
Sonuç ve Tartışma: Moleküler yerleştirme çalışması sonucunda, Doravirin (bileşik 3), Etravirin (bileşik 6) ve Rilpivirin’in (bileşik 9) referans TERT inhibitörü BIBR1532'ye kıyasla TEN alanına daha yüksek bağlanma potansiyeli ile bağlandığını ortaya koymuştur. MD simülasyon çalışması ile, protein-Doravirin kompleksinin proteinin bağlanma cebindeki en yüksek stabiliteye sahip olduğu gösterilmiştir. Öte yandan, protein-Rilpivirin kompleksinin kararlı olmaması nedeniyle bağlanma cebinde kalmama ihtimali bulunmaktadır. Yapılan çalışma, Doravirin’in TEN’i inhibe edebileceğini göstermiştir. Bu nedenle, Doravirin'in TERT'in TEN alanını inhibe ederek antikanser potansiyel gösterebilme ihtimali nedeniyle Doravirin türevi yeni bileşiklerin tasarlanması ve sentezlenmesi düşünülmektedir.

Keywords

MD simülasyon, moleküler yerleştirme, NNRTI, NRTI, TERT

INVESTIGATION OF THE INHIBITORY POTENTIAL OF SOME ANTIVIRAL AGENTS ON HUMAN TELOMERASE BY MOLECULAR DOCKING AND MOLECULAR DYNAMICS SIMULATION STUDIES

Abstract

Objective: This study investigated the anticancer effects of nucleoside and non-nucleoside reverse transcriptase inhibitors drugs by computational methods. The study aimed to evaluate the binding capacity of these drugs on the telomerase essential N-terminal (TEN) domain of telomerase reverse transcriptase (TERT). Molecular docking was used to assess the drugs' binding potential to the TEN domain. The stability of the protein-drug combination obtained from the docking method was assessed using molecular dynamics (MD) simulation.
Material and Method: The TEN domain of TERT's crystal structure was obtained from the Protein Data Bank (PDB). The crystal structure identified by the PDB code 2B2A has a resolution of 2.2 Å. The molecular docking was performed using AutoDock Vina. The complexes were visualized using Biovia Discovery Studio. The MD simulation was conducted using GROMACS 2020 as indicated. An MD simulation was conducted for 200 ns on both the complexes and the free protein. The RMSD (root mean square deviation) of the backbone protein and the molecules in relation to the backbone protein, RMSF (root mean square fluctuation), and Rg (radius of gyration) were shown via Qt Grace.
Result and Discussion: Doravirine, Etravirine, Rilpivirine showed higher binding affinity to the TEN domain compared to the reference TERT inhibitor, BIBR1532, based on the docking investigation. The MD simulation analysis showed that the protein-Doravirine complex had the highest stability in remaining within the protein's binding pocket. On the contrary, the protein-Rilpivirine complex decreased stability, potentially causing the ligand to not to stay within the binding site. Doravirine was found to inhibit the TEN domain in the computational study. Therefore, the design and synthesis of novel doravirin derivatives is being considered because of the potential anticancer activity of doravirin in inhibiting the TEN domain of TERT.

Keywords

MD simulation, molecular docking, NNRTI, NRTI, TERT

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