IN SILICO EVALUATION OF SARS-COV-2 PAPAIN-LIKE PROTEASE INHIBITORY ACTIVITY OF SOME FDA-APPROVED DRUGS

Öz

Objective: In this study, it was aimed to perform in silico studies on the papain-like protease structure of SARS-CoV-2 (PDB: 7JIT) of 1300 FDA-approved drugs downloaded from the ZINC database. Material and Method: A molecular docking study was performed with PLpro (PDB ID: 7JIT) using four different molecular docking programs for a total of 1300 FDA-approved drugs obtained from the ZINC database. Conivaptan and amphotericin B were obtained in docking analysis with AutoDock Vina and Sybyl-X, respectively. Docking analysis with Glide SP and Glide XP resulted in fludarabine and panobinostat, respectively. Molecular dynamics simulations were performed for a period of 120 ns to check the stability of these four drugs. Result and Discussion: The reliability of the results obtained using four different molecular docking programs on the SARS-CoV-2 papain-like protease of 1300 drug molecules was checked by reinserting the co-crystal ligand. Protein-ligand interactions between fludarabine, conivaptan, amphotericin-B, panobinostat, and PLpro were given. In the molecular dynamics study, RMSD, RMSF, Rg, and SASA analyses were performed for four systems. It was observed that RMSD remained constant for all 120 ns for all four systems except for amphotericin B, which deviated slightly towards the end of 120 ns. No significant fluctuation was noticed in the RMSF graphics for all four systems.

Anahtar Kelimeler

• Molecular docking
• molecular dynamics
• SARS-CoV-2
• ZINC

Teşekkür

All molecular dynamics simulations reported were performed utilizing TÜBİTAK (The Scientific and Technological Research Council of Turkey) ULAKBİM (Turkish Academic Network and Information Centre), High Performance and Grid Computing Centre (TRUBA resources).

FDA ONAYLI BAZI İLAÇLARIN SARS-COV-2 PAPAİN-LİKE PROTEAZ İNHİBİTÖR AKTİVİTESİNİN İN SİLİKO DEĞERLENDİRİLMESİ

Öz

Amaç: Bu çalışmada ZINC veri tabanından indirilen 1300 adet FDA onaylı ilacın SARS-CoV-2'nin papain-like proteaz yapısı üzerinde (PDB:7JIT) in siliko çalışmalarının yapılması amaçlanmıştır. Gereç ve Yöntem: ZINC veri tabanından elde edilen toplam 1300 FDA onaylı ilaç, dört ayrı moleküler doking programı kullanılarak PLpro (PDB ID: 7JIT) ile moleküler doking çalışması gerçekleştirildi. AutoDock Vina ve Sybyl-X ile doking analizinde, sırasıyla conivaptan ve amfoterisin B elde edildi. Glide SP ve Glide XP ile doking analizi sırasıyla fludarabin ve panobinostat ile sonuçlandı. Bu dört ilacın stabilitelerini kontrol etmek için 120 ns'lik bir süre boyunca moleküler dinamik simülasyonları gerçekleştirildi. Sonuç ve Tartışma: 1300 ilaç molekülünün SARS-CoV-2 papain benzeri proteazı üzerinde dört farklı moleküler doking programı kullanılarak elde edilen sonuçların güvenilirliği, ko-kristal ligandın yeniden yerleştirilmesiyle kontrol edildi. Fludarabin, conivaptan, amphotericin-B, panobinostat ve PLpro arasındaki protein-ligand etkileşimleri verildi. Moleküler dinamik çalışmasında dört sistem için RMSD, RMSF, Rg ve SASA analizleri yapıldı. 120 ns'nin sonlarına doğru hafifçe sapan amfoterisin B hariç, RMSD'nin dört sistemde de 120 ns'nin tamamında sabit kaldığı gözlendi. Dört sistemin tümü için RMSF grafiklerinde önemli bir dalgalanma fark edilmedi.

Anahtar Kelimeler

• Moleküler dinamik
• moleküler doking
• SARS-CoV-2
• ZINC

Kaynakça

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