In CovPDB, you can quickly view the list of all ligands, proteins, complexes, warheads, covalent mechanisms, and targetable residues by clicking one of the six main representative icons on the homepage.
There is the possibility to search for compounds ordered alphabetically. To do so, navigate to Home -> Browse -> Ligands (List) and you could also find the related information of the ligand, like structures and the number of complexes.
Click on the Proteins icon on the homepage or Home -> Browse -> Proteins.
Click on the Complexes icon on the homepage or Home -> Browse -> Complexes.
There is a Warheads icon on the homepage or you can go Home -> Browse ->Warheads which you could browse all the Warheads SMARTS and Structures that formed covalent bonds with targetable residues.
Click on the Mechanisms icon on the homepage or Home -> Browse -> Cov. Mechanisms. A table will be displayed for all the 21 different mechanism types.
Click on the Residues icon on the homepage or Home -> Browse -> Targetable Residues. A table will be displayed for all the 14 different targetable residues.
If you know the name of the ligand of interest, you could go Home -> Search ->Name/ID ->Ligand Name/HET Code/Ligand ID, then just input the HET Code, ligand name, or synonym.
Sometimes, the name of a compound is not clearly defined or not known, but the structure of the compound is known. In that case, it is possible to draw the structure by using the ChemDoodle structure editor. It is not necessary to match the exact structure, similar structures will also be identified.
If you know the name of the protein of interest, sers can try Home -> Search ->Name/ID ->Protein Name, then just input the protein name or synonym.
Or if you know the UniProt ID or Entry Name of the protein of interest, you can also search through Home -> Search ->Name/ID ->Uniprot ID/ACC.
If you know the PDB ID of the complex of interest, you can try Home -> Search ->Name/ID ->PDB ID, then just input the PDB ID and will be led to a complex card of this PDB entry.
Sequence Similarity Searching of CovPDB uses BLAST+ tool to perform fast local alignment searches for a query sequence. For a sequence of interest, navigate to Home -> Search -> Name/ID -> Sequence, just type in a query sequence without header.
The search result page displays an overview of all the retrieved hits with their corresponding scoring. Below the table, a more detailed alignment result is displayed.
It is possible to change the search parameters e.g. decreasing the tanimoto coefficient in order to increase the number of retrieved similar compounds. Additionally, you can decide to search for substructures, e.g. you can draw a tricyclic structure to retrieve all tricyclic compounds contained in the CovPDB database.
Ligand similarity searches in CovPDB are conducted with RDKit using Morgan fingerprints or substructure searches. Those fingerprints represent structural features of a molecule. Fingerprints are dichotomous [0,1] (bit) arrays. CovPDB uses the tanimoto coefficient for similarity calculations:
CovPDB freely provides its content as separate files for download, namely, all ligand structures (SDF format), protein sequences (FASTA format)protein-ligand complexes (PDB format), and reactive warheads (TXT format).
CovPDB cites data from the following public resources:
The COVPDB ID is a unique ID that has been assigned to ligands in CovPDB. It can be used to retrieve a Ligand Card page for these entities.
The data of CovPDB will be updated periodically to include more entries upon the availability of newly deposited 3D models in the PDB.
To the best of our knowledge, CovPDB is the first freely accessible web database solely dedicated to high-resolution 3D structures of biologically relevant covalent protein–ligand complexes, mined from the Protein Data Bank. CovPDB describes 2,294 covalent complexes, 1,501 covalent ligands, 733 associated protein targets, 93 reactive warheads, 21 covalent mechanisms, and 14 targetable residues.
The application of quantum chemistry to study the mechanism of action of covalent complexes is a general and versatile approach. We have collected 93 different warheads and high-resolution PDB structures in our database. Therefore, researchers can use the data from CovPDB to apply the QM/MM or QM method to study enzyme reaction and warhead reactivity.
Covalent ligands/inhibitors are considered to be an important part of drug discovery and therapeutics. Thousands of co-crystal structures deposited in CovPDB provide comprehensive information for structure-based covalent ligand design for a protein of interest. Different covalent docking tools are be used to do covalent docking. You could find the high-resolution 3D covalent protein structures from the Download section which can be directly applied to a covalent docking.
Conserved sequence motifs and homology modeling studies could be performed with the protein sequences.
SASA and pKa values were calculated with FreeSASA and PROPKA programs, respectively.
FreeSASA is an open source library for calculating solvent accessible surface areas (SASA) of protein, RNA and DNA molecules. We calculated SASA of targetable residues directly from PDB files using default parameters.
PROPKA (version 3) predicts the local pKa values of targetable amino acid residue of protein ionizable groups depending on the desolvation and dielectric response for the protein.
Mingjie Gao, Aurélien F A Moumbock, Ammar Qaseem, Qianqing Xu, Stefan Günther
CovPDB: a high-resolution coverage of the covalent protein–ligand interactome. Nucleic Acids Research. 2022 Jan 7;50(D1):D445-D450.
doi: 10.1093/nar/gkab868. PMID: 34581813; PMCID: PMC8728183.