Abstract
Covid-19 is caused by a novel form of coronavirus for which there are currently no vaccines or anti-viral drugs. This virus, termed SARS-CoV-2 (CoV2), contains Papain-like protease (PLpro) involved in viral replication and immune response evasion. Drugs targeting this protease therefore have great potential for inhibiting the virus, and have proven successful in older coronaviruses. Here, we introduce two effective inhibitors of SARS-CoV-1 (CoV1) and MERS-CoV to assess their potential for inhibiting CoV2 PLpro. We ran 1 μs molecular dynamics (MD) simulations of CoV2, CoV1, and MERS-CoV ligand-free PLpro to characterize the dynamics of CoV2 PLpro, and made comparisons between the three to elucidate important similarities and differences relevant to drug design and ubiquitin-like protein binding for deubiquitinating and deISGylating activity of CoV2. Next, we simulated the inhibitors bound to CoV1 and CoV2 PLpro in various poses and at different known binding sites to analyze their binding modes. We found that the naphthalene-based ligand shows strong potential as an inhibitor of CoV2 PLpro by binding at the putative naphthalene inhibitor binding site in both computational predictions and experimental assays. Our modeling work suggested strategies to improve naphthalene-based compounds, and our results from molecular docking showed that the newly designed compounds exhibited improved binding affinity. The other ligand, chemotherapy drug 6-mercaptopurine (6MP), showed little to no stable intermolecular interaction with PLpro and quickly dissociated or remained highly mobile. We demonstrate multiple ways to improve the binding affinity of the naphthalene-based inhibitor scaffold by engaging new residues in the unused space of the binding site. Analysis of CoV2 PLpro also brings insights into recognition of ubiquitin-like proteins that may alter innate immune response.
Highlights
Covid-19, caused by a novel form of coronavirus, has created a global health crisis due to the lack of vaccines and anti-viral drugs
SUb1 contains hydrophobic residues that contact the ligand in the 3k binding site, while SUb2 is adjacent to the highly mobile UBL domain and is affected by contacts to its Ub-interacting residues brought about by UBL domain rotation
3k and 6MP, known to inhibit CoV1 and MERS-CoV Papain-like protease (PLpro), respectively, into CoV2 PLpro to assess their ability as CoV2 inhibitors and identify opportunities for further optimization of the ligand scaffolds
Summary
Covid-19, caused by a novel form of coronavirus, has created a global health crisis due to the lack of vaccines and anti-viral drugs. Development of anti-viral drugs capable of inhibiting CoV2 is of paramount importance. CoV2 contains a Papain-like protease (PLpro) that is vital for viral replication (Harcourt et al, 2004). PLpro is responsible for the proteolytic processing of the product of open reading frame 1a (ORF1a) in the replicase gene of CoV2, a large viral polyprotein containing non-structural proteins which form the replicase complex (Wertz and Murray, 2019). Inhibition of PLpro activity can halt viral replication and disrupt its role in host immune response evasion, making it an excellent anti-viral drug target
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