In Silico Screening of the Phenolic Compound Oleuropein and Its Hydrolysis Product 3-Hydroxytyrosol Against Certain Structural and Non-Structural Proteins of SARS-CoV- 2

Year 2021, Volume: 8 Issue: 3, 824 - 833, 26.07.2021

Erman Salih İstifli

https://doi.org/10.30910/turkjans.953603

Cited By: 1

Abstract

The novel corona virus has infected nearly 163 million people globally as of May 2021 and caused death of more than 3.3 million patients. Despite intense efforts, however, a small molecule with full therapeutic potential has not been developed in the treatment of SARS-CoV-2. The aim of this study was to investigate the inhibitory potentials of oleuropein and its hydrolysis product 3-hydroxytyrosol against spike glycoprotein, papain-like protease, main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular modelling simulations. Compared to 3-hydroxytyrosol, oleuropein showed stronger binding affinity to all targets in docking, and its affinity to Mpro (-7.0 kcal mol-1) and RdRp (-8.0 kcal mol-1) was quite high. Despite the Mpro-oleuropein complex, the RdRp-oleuropein complex showed a highly stable binding in 15-ns molecular dynamics based on root-mean-square-deviation (0.14 - 0.32 nm) and hydrogen bond numbers (6.85). The intracellular targets of oleuropein covered various proteases (17%), enzymes (16%), family A G protein-coupled receptors (11%), kinases (10%) and other cytosolic proteins (10%), however, probabilistic analysis showed that oleuropein was unlikely (p = 0 - 0.22) to bind these targets. ADMET profile showed that, with few exceptions, oleuropein has the physicochemistry that should be present in a drug molecule. In conclusion, oleuropein binds tightly to the active site of RdRp and could inhibit this enzyme. Oleuropein may be used alone or in combination with replicase inhibitors such as remdesivir or favipiravir in the treatment of COVID-19. Additional in vitro binding assays and in vivo efficacy studies are needed to prove our findings.

Keywords

Oleuropein, 3-hydroxytyrosol, SARS-CoV-2, Molecular docking, Molecular dynamics

Fenolik Bileşik Oleuropein ve Hidroliz Ürünü 3-Hidroksitirozol'ün SARS-CoV-2'nin Bazı Yapısal ve Yapısal Olmayan Proteinlerine Karşı In Siliko Etkinliği

Abstract

Yeni tip korona virüsü Mayıs 2021 itibariyle dünya genelinde yaklaşık 163 milyon kişiyi enfekte etmiş ve 3.3 milyondan fazla hastanın ölümüne neden olmuştur. Yoğun çalışmalara rağmen SARS-CoV-2 tedavisinde tam koruma sağlayan terapötik potansiyelli bir ilaç geliştirilememiştir. Bu çalışmanın amacı, moleküler modelleme simülasyonları kullanarak oleuropein ve onun hidroliz ürünü 3-hidroksitirosol’ün SARS-CoV-2 spike glikoproteini, papain-benzeri proteazı (PLpro), ana proteazı (Mpro) ve RNA-bağımlı RNA polimerazına (RdRp) karşı inhibitör potansiyellerini araştırmaktır. 3-hidroksitirosol ile karşılaştırıldığında oleuropein, moleküler doking analizinde tüm protein hedeflere daha yüksek bağlanma afinitesi göstermekle beraber Mpro (-7.0 kcal/mol) ve RdRp'ye (-8.0 kcal/mol) karşı afinitesi oldukça yüksek bulunmuştur. Kök-ortalama-kare-sapması (0.14 - 0.32 nm) ve hidrojen bağı sayısı (6.85) göz önüne alındığında, Mpro-oleuropein kompleksinin aksine, RdRp-oleuropein kompleksi 15 nanosaniyelik moleküler dinamik analizinde oldukça kararlı bir bağlanma sergilemiştir. Oleuropein’in intraselüler hedefleri arasında çeşitli proteazlar (%17), enzimler (%16), G protein-bağlı reseptörler (%11), kinazlar (%10) ve diğer sitozolik proteinler (%10) bulunmasına rağmen, olasılık analizlerine göre oleuropein’in bu hedeflere bağlanma olasılığı oldukça düşük bulunmuştur (p = 0 - 0.22). Birkaç istisna dışında oleuropein'in absorbsiyon-dağılım-metabolizma-atılım-toksisite (ADMET) profili, bir ilaç molekülünde bulunması gereken fizikokimyasal özelliklere sahip olduğunu göstermiştir. Sonuç olarak oleuropein, RdRp'nin aktif bölgesine sıkıca bağlanma ve bu enzimi inhibe etme potansiyeline sahiptir. Oleuropein, COVID-19 tedavisinde tek başına ya da remdesivir veya favipiravir gibi replikaz inhibitörleri ile birlikte kullanılabilir. Bulgularımızın kanıtlanması için ilave in vitro ilaç-bağlanma ve in vivo etkinlik çalışmalarına ihtiyaç duyulmaktadır.

Keywords

Oleuropein, 3-hidroksitirosol, SARS-CoV-2, RdRp, Moleküler doking, Moleküler dinamik

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