Druggability of Cavity Pockets within SARS-CoV-2 Spike Glycoprotein and Pharmacophore-based Drug Discovery
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Ali Salehnia sammak,1 Alireza Mohebbi,2,*
1. Department of Microbiology, Rasht Branch, Islamic Azad University, Rasht, Iran
2. Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, 4934174515, Gorgan, Iran
- Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current COVID-19 pandemic. Researchers identified several viral proteins in SARS‐CoV‐2 as therapeutic targets, including S protein, envelope (E) protein, membrane (M) protein, nucleocapsid protein (N), proteases (3C-like protease (3CLpro), papain-like protease (PLpro)), Nsp1, Nsp3 (Nsp3b, Nsp3c, Nsp3e), Nsp7 Nsp8 complex, Nsp9–Nsp10, and Nsp14–Nsp16, ORF7a, helicase, RNA-dependent polymerase (RdRp) [10,11]. Among them, the S protein gained more attention due to its role in the entry of the virus. S protein contains two domains S1 and S2 [12]. The S1 domain has a significant role to play in virus entry.Virus spike glycoprotein is a good target for drug discovery. The purpose of this research was to examine the potential for druggability of Spike protein for pharmacophore-based drug discovery.
- Methods: Predicted 3D viral protein structure was investigated in druggable cavities using CavityPlus. A pharmacophore was extracted from the druggable cavity and used for hit identification. Autodock Vina was used to evaluate the affinities of match hits for lead identification. A chemical library was also built from the chemical backbone to optimize the lead compound.
- Results: 42 cavities were found within the virus Spike glycoprotein and five of them were druggable .The druggable cavity No.1 with highest Drug score (10041) was selected for pharmacophore modeling.
Ten druggable cavities were found within the glycoprotein spike. Only one cavity with the highest score at the binding site was selected for pharmacophore extraction. Hit identification of a virtual library containing more than 1 billion natural product compounds resulted in the identification of 410 hits. One chemical (Compound38) was found to have the highest affinity to SARS-CoV-2. Drug-likeness and ADME properties of the chemical library was predicted by SwissADME [31] and is provided in the supplemented materials . Accordingly, no significant toxicity was observed.
- Conclusion: this study provides a druggable region within viral glycoprotein and a candidate compound to block viral entry.In the first place, this study provides a comprehensive search for significant drug-gable cavities within SARS-CoV-2. Second, a virtual library containing millions of natural products has been screened. Third, chemical candidates were developed to block viral entry by interacting with the binding domain of viral spike glycoprotein. The findings of the study presented may be used in future studies on COVID-19 therapy.
- Keywords: SARS-CoV-2; COVID-19; Spike protein; Virtual screening; Docking
