COVID-19 Docking Server
A web server for docking small molecule, peptide or antibody to COVID-19 protein targets.
Main protease (Mpro): It is also named as chymotrypsin-like protease (3CLpro). Mpro cleaves most of the sites in the polyproteins and the products are nonstructural proteins (nsps) which assemble into the replicase-transcriptase complex (RTC). The crystal structure of Mpro in complex with an inhibitor N3 was downloaded from the PDB database with code of 6LU7 . The target is prepared both for small molecule docking and peptide/antibody docking.
Papain-like protease (PLpro): PLpro cleaves the nsp1/2, nsp2/3 and nsp3/4 boundaries. It works with Mpro to cleave the polyproteins into nsps. The crystal structure of PLpro in complex with peptide inhibitor VIR250 was downloaded from the PDB database with code of 6WUU . As the inhibitor is bound to the interface of dimer in the crystal structure, the dimer form of the target is prepared for small molecule docking. For peptide/antibody docking, both the dimer form and the monomer form are provided on the server.
Helicase (Nsp13): The helicase catalyzes the unwinding of duplex oligonucleotides into single strands in an NTP-dependent manner. It is also an ideal target to develop anti-viral drugs due to its sequence conservation in all CoV species. The structure of helicase was built based on 6JYT, the helicase structure of SARS-CoV  with sequence identity as 98.5%. Two sites were described as ADP binding site and nucleic acid binding site by comparing the structure with its homolog ATP-dependent helicase from Saccharomyces cerevisiae with PDB code of 2XZL . Thus we defined two sites for small molecule docking: the ADP binding site (ADP site), and the nucleic acids binding site (NCB site) and prepared the target structure. Helicase is also provided for peptide or antibody docking.
Nonstructural protein 12/7/8 (nsp12/7/8, RNA-dependent RNA polymerase, RdRp): Nsp12 is the polymerase which bounds to its essential cofactors, nsp7 and nsp8. It is important in replication and transcription of the viral genome. The structure of RdRp in complex with RNA and triphosphate form of Remdesivir (RTP) was downloaded from PDB database with code of 7BV2 . Thus we defined two sites for small molecule docking: the RTP binding site (RTP site), and the RNA binding site (RNA site) and prepared the target structure. For peptide or antibody docking, four structures were provided: the complex form of nsp12/7/8, and the single chain of nsp12, nsp7, and nsp8.
Nonstructural protein 14 (N-terminal exoribonuclease and C-terminal guanine-N7 methyl transferase, nsp14): Nsp14 of coronaviruses (CoV) is important for viral replication and transcription. The N-terminal exoribonuclease (ExoN) domain plays a proofreading role for prevention of lethal mutagenesis, and the C-terminal domain functions as a guanine-N7 methyl transferase (N7-MTase) for mRNA capping. The structure of nsp14 was built based on 5C8S, the nsp14 structure of SARS-CoV, with sequence identity as 92%. Two sites were prepared for small molecule docking. The active site of C-terminal N7-MTase is defined as SAH binding site in 5C8S. To define the active site of ExoN, the structure of its homolog 1J53 from Escherichia coli in complex with thymidine 5'-monophosphate (TMP) was aligned to the ExoN of SARS-CoV2 [7, 8]. Thus the docking box was set to the center of the transformed coordinates of TMP with 30Å×30Å×30Å in length to include the residues of entire cavity. The full length of nsp14 is also provided for peptide or antibody docking on the server.
Nonstructural protein 15 (Uridylate-specific endoribonuclease): Nsp15 forms a hexameric endoribonuclease that preferentially cleaves 3' of uridines, also named as Uridylate-specific endoribonuclease. It is one of the RNA-processing enzymes encoded by the coronavirus. The structure of nsp15 in complex with Uridine-5'-Monophosphate was downloaded from the PDB database with code of 6WLC . The target is prepared both for small molecule docking and peptide/antibody docking.
Nonstructural protein 16/10 (nsp16/10, 2'-O-methyltransferase): Nsp16 is a S-adenosylmethionine (SAM) dependent nucleoside-2’-O methyltransferase. It is only active with the binding of nsp10. The structure of nsp16/10 in complex with 7-methyl-GpppA (GTA), S-Adenosylmethionine (SAM), and 7-methyl-guanosine- 5'-triphosphate (MGP) was downloaded from the PDB database with code of 6WVN . As there are three ligands binding in different region of the protein, these sites are defined for small molecule docking and named as GTA_site, SAM_site and MGP_site on the sever. The complex form of nsp16/10, and the single chain of nsp16, nsp10 are provided for peptide or antibody docking.
Nonstructural protein 3 (nsp3, range: 207-379): The crystal structure of ribose phosphatase domain of NSP3 from SARS CoV-2 in complex with Adenosine Monophosphate (AMP) and 2-(N-morpholino)-ethanesulfonic acid (MES) was downloaded from the PDB database with the code of 6W6Y . As there are two ligands binding in different regions of the protein, two binding sites are defined for small molecule docking and named as AMP_site and MES_site. The protein structure is also provided for peptide or antibody docking on the server.
Nonstructural protein 9 (nsp9): It may act as ssRNA-binding protein in viral replication. Littler et al. resolved the crystal structures of nsp9 in dimer and monomer form with PDB code of 6WXD and 6W9Q, respectively . The N terminal residues in dimer present as anti-parallel β-sheet conformation while these residues form extended loop conformation in the monomer. Thus two states of nsp9 are provided for peptide or antibody docking.
Open Reading Frame (ORF) 7A: The crystal structure accessory protein of SARS CoV-2 encoded by ORF7A was downloaded from the PDB database with the code of 6W37 . The target is provided for peptide or antibody docking on the server.
The predicted structural models of the other nsp proteins or ORF proteins without experimental structures available currently were downloaded from the Zhang’s lab from the University of Michigan, including nsp1, nsp2, nsp4, nsp6, ORF3A, ORF6, ORF8 and ORF10 . These targets are provided for peptide or antibody docking on the server.
The spike protein (S): The surface spike glycoprotein is consisting of three S1-S2 heterodimers. The receptor binding domain (RBD) located on the head of S1 and bind with the cellular receptor angiotensin-converting enzyme 2 (ACE2), initiating the membrane fusion of the virus and host cell. The structure of spike RBD of SARS-CoV-2 in complex with human ACE2 was released by Wang and Zhang’s group in Tsinghua University with PDB code of 6M0J . The full length structure of spike protein was also determined by using the electron microscopy method. It is shown that the spike protein forms trimer and presents two differential conformations: open state and close state . Thus for spike protein, we provided the RBD domain from 6M0J, the open state of trimer from 6VYB, the close state of trimer from 6VXX, the open state of monomer from 6VYB and the close state of monomer from 6VXX for peptide or antibody docking.
S2 of S protein: It is the post-fusion state of S2 segment of spike protein, acting as viral fusion protein to mediate the membrane fusion of virus and cells. Typical HR1/HR2 6-helices complex were formed as post-fusion state of SARS-CoV-2, similar to the fusion step of HIV-1 virus. It is a potential target for entry inhibitor development. The 6-helices post fusion conformation of S2 was downloaded from the PDB database with the code of 6LXT . A 5-helices structure was prepared by deleting one of the helix from the 6-helices structure and used as receptor for peptide or antibody docking.
Envelop small membrane protein (E protein): It forms pentamer and functions as ion channel, also named as E channel. The modeled structure of E protein was downloaded from the Zhang’s lab and prepared for peptide or antibody docking.
Membrane protein (M protein): The M protein involves in most of protein-protein interactions required for assembly of coronaviruses and it is also determined as a protective antigen in humoral responses. The structure of M protein was downloaded from the Zhang’s lab and prepared for peptide or antibody docking .
Nucleocapsid protein (N protein): N protein plays multiple roles in the virus replication cycle and forms a ribonucleo protein complex with the viral RNA through the N protein's N-terminal domain (N-NTD). It buds the viral genomes into the membrane of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) containing the viral structure proteins to form the mature virions finally . The full length structure of N protein was downloaded from the Zhang’s lab and prepared for peptide or antibody docking . Recently, the N-terminal RNA-binding domain and C-terminal dimerization domain of N protein are also released in the PDB database. 6YI3 (N-terminal domain) and 6YUN (C-terminal domain) are prepared and provided for peptide or antibody docking on the server [19, 20]. The ribonucleotide-binding site (NCB site) of N protein was built based on the complex structure of N protein from Human coronavirus OC43 with the PDB code of 4KXJ with sequence identity of 47.0% and similarity as 62.0%, and prepared for small molecule docking .
Angiotensin-converting enzyme 2 (ACE2): The structure of human ACE2 was extracted from the complex structure of SARS-CoV-2 spike RBD and human ACE2 released by Wang and Zhang’s group in Tsinghua University with PDB code of 6M0J and prepared for peptide or antibody docking .
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