The Virtual Screening and Molecular Docking Study of New Inhibitors for SARS-COV-2 Papain-Like Protease (PLpro)

Abstract

Although global human mobility has normalized after the COVID-19 pandemic, the disease remains a major threat due to the emergence of new variants, keeping it a key target for drug development. Considerable efforts have been put to understand the disease, to create treatment options, and ultimately to eradicate it. It has been shown that these viruses have the largest genome size among all known RNA viruses, with their genome consisting of an RNA strand enclosed in a protein coat. PLpro is an enzymatic protein which is necessary for the replication process of SARS-CoV-2 and during viral infection, it is essential in helping coronaviruses evade the host's innate immune defense. Consequently, targeting PLpro in antiviral drug development could be an effective approach to inhibit viral replication and interfere with signaling pathways in infected cells. This study aims to provide new potential inhibitor candidates for PLpro (PDB: 7LOS) by molecular modelling study. A total of over 2 million molecules from ZINC15 database have been screened against PLpro by structure- based virtual screening, followed by molecular docking. The docking scores of the top five ligands were in the range of -81.57 kcal/mol and -83.19 kcal/mol, which were much better than that of co-crystallized ligand Y97 (-58.25 kcal/mol). The docking results indicated that ligands interact with the key residues (Asp 164, Arg 166, and Glu167) in the active pocket of PLpro. H02 revealed some physicochemical properties as a potential hit according to the ADME results.

Keywords

• SARS-CoV-2
• PLpro inhibitors
• virtual screening
• molecular docking
• drug design

Supporting Institution

TUBİTAK (Türkiye Bilimsel ve Teknolojik Araştırma Kurumu), TUBİTAK ULAKBIM (TRUBA Resources)

Thanks

The author (AAB) would like to thank TUBİTAK (Türkiye Bilimsel ve Teknolojik Araştırma Kurumu) due to the postgraduate scholarship in the scope of 2211-C. Authors are also grateful to TUBİTAK ULAKBIM, High Performance and Grid Computing Center, for allowing the use of (TRUBA resources) during the molecular docking process.

SARS-COV-2 Papain Benzeri Proteaz (PLpro) İçin Yeni İnhibitörlerin Sanal Tarama ve Moleküler Yerleştirme Çalışması

Abstract

COVID-19 salgını sonrasında küresel insan hareketliliği normale dönmüş olsa da, hastalık yeni varyantların ortaya çıkması nedeniyle büyük bir tehdit olmaya devam ediyor. Bu sebeple, hastalığı anlamak, tedavi seçenekleri oluşturmak ve nihayetinde ortadan kaldırmak için önemli çabalar sarf edilmektedir. Bu virüslerin, bilinen tüm RNA virüsleri arasında en büyük genom boyutuna sahip olduğu ve genomlarının bir protein kılıfı içinde bulunan bir RNA ipliğinden oluştuğu kanıtlanmıştır. PLpro, SARS-CoV-2'nin replikasyon süreci için gerekli olan enzimatik bir proteinidir ve viral enfeksiyon sırasında koronavirüslerin konağın doğuştan gelen bağışıklık savunmasından kaçmasına yardımcı olmakta görevlidir. Sonuç olarak, antiviral ilaç geliştirmede PLpro'yu hedeflemek, viral replikasyonu inhibe etmek ve enfekte hücrelerdeki sinyal yollarına müdahale etmek için etkili bir yaklaşım olabilir. Bu çalışma, moleküler modelleme çalışmasıyla PLpro (PDB: 7LOS) için yeni potansiyel inhibitör adayları sağlamayı amaçlamaktadır. ZINC15 veritabanından 2 milyondan fazla molekül, yapı tabanlı sanal tarama ve ardından moleküler yerleştirme ile PLpro'ya karşı tarandı. İlk beş ligandın yerleştirme puanları, eş-kristalize ligand Y97'nin (-58,25 kcal/mol) puanlarından çok daha iyi olan -81,57 kcal/mol ve -83,19 kcal/mol aralığındaydı. Yerleştirme sonuçları, ligandların PLpro'nun aktif cebindeki anahtar kalıntılarla (Asp 164, Arg 166 ve Glu167) etkileşime girdiğini gösterdi. ADME sonuçlarına göre H02, potansiyel bir hedef olarak bazı fizikokimyasal özellikler ortaya koydu.

Keywords

• SARS-CoV-2
• PLpro inhibitörleri
• sanal tarama
• moleküler yerleştirme
• ilaç tasarımı

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