RNA-DEPENDENT RNA POLYMERASE (RDRP) INHIBITOR DRUGS AGAINST SARS-COV-2: A MOLECULAR DOCKING STUDY

Abstract

Objective: SARS-CoV-2 associated viral pandemic was first reported in Wuhan, China, in December 2019. Due to the rapid increase in its pathogenicity, SARS-CoV-2 was declared a global pandemic by WHO on March 11, 2020. For that reason, determining the most attractive viral protein targets became a must. One of the most important target proteins is SARS-COV-2 RNA-dependent RNA polymerase (RdRp) on which COVID-19 depends in its replication process. This study aimed to examine the possible interactions between RdRp and the most promising RdRp nucleoside inhibitors especially Purine nucleoside analogs, to detect the most important residues that commonly interact with RdRp's inhibitors and to investigate whether if there any mutations have been observed so far in these residues or not.
Material and Method: Molecular docking studies were carried out using AutoDock Vina between SARS-CoV-2 RdRp and drugs approved against different viral RdRps (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir, and Favipiravir) as well as physiological nucleotides (ATP and GTP). Based on the obtained results, a detailed surface-interaction analysis was also performed using Pymol and Discovery Studio Visualizer software for the models that exhibited the most suitable location and configuration in space.
Result and Discussion: All the tested molecules were able to bind to SARS-CoV-2 RdRp successfully. Also, they all commonly interact with 9 different amino acids (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760, and Asp761), and 3 different Template-primer RNA nucleotides (U10, A11, and U20) causing inhibition of viral RdRp via non obligate RNA chain termination.

Keywords

• COVID-19
• molecular docking
• RdRp
• nucleotide analogs

SARS-COV-2'YE KARŞI RNA-BAĞIMLI RNA POLİMERAZ (RDRP) İNHİBİTÖR İLAÇLARI: BİR MOLEKÜLER DOCKİNG ÇALIŞMASI

Abstract

Amaç: SARS-CoV-2 ile ilişkili viral pandemisi ilk olarak Aralık 2019'da Çin'in Wuhan kentinde bildirilmiştir. enfeksiyon gücünün yüksek olması nedeniyle, Dünya Sağlık Örgütü (DSÖ) 11 Mart 2020 tarihinde SARS-CoV-2’yi küresel pandemi olarak ilan etmiştir. Bu nedenle en önemli viral protein hedeflerinin belirlenmesi bir zorunluluk haline geldi. En önemli hedef proteinlerden biri ise, SARS-COV-2’nin replikasyon sürecinin bağlı olduğu RNA'ya bağımlı RNA polimerazdır (RdRp). Bu çalışmada RdRp ile RdRp nükleozit inhibitörleri, özellikle de Purin nükleozid analogları arasındaki olası etkileşimlerin incelenmesi, RdRp inhibitörleri ile yaygın olarak etkileşime giren en önemli kalıntıların saptanması ve bu kalıntılarda şimdiye kadar herhangi bir mutasyon gözlemlenip gözlemlenmediği araştırılması amaçlanmıştır.
Gereç ve Yöntem: SARS-CoV-2 RdRp’ye karşı fizyolojik nükleotidler (ATP ve GTP) ve farklı viral RdRpler’e karşı onaylanmış ilaçlar (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir ve Favipiravir) olmak üzere toplam 7 bileşik test edilmiştir. RdRp ile bu 7 bileşik arasında AutoDock Vina yardımıyla moleküler docking çalışmaları gerçekleştirilmiş olup moleküler docking çalışmalarından elde edilen sonuçlara ve uzaydaki konfigürasyonlarına göre en uygun olan modelleri için de detaylı yüzey etkileşim analizi Pymol ve Discovery Studio Visualizer software yardımıyla yapılmıştır.
Sonuç ve Tartışma: Test edilen tüm moleküller, SARS-CoV-2 RdRp'ye başarıyla bağlanabilmiştir. Ayrıca hepsi 9 farklı amino asit ile (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760 ve Asp761) aynı zamanda 3 farklı Template-primer RNA nükleotidi (U10, A11 ve U20) ile etkileşime girmiş ve zorunlu olmayan RNA zinciri sonlandırması yoluyla viral RdRp'nin inhibisyonuna neden olmuşlardır.

Keywords

• COVID-19
• moleküler docking
• RdRp
• nükleotid analogları

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