CovBinderInPDB: A Structure-Based Covalent Binder Database

Abstract

Covalent inhibition has emerged as a promising orthogonal approach for drug discovery, despite the significant challenge in achieving target specificity. To facilitate the structure-based rational design of target-specific covalent modulators, we developed an integrated computational protocol to curate covalent binders from the RCSB Protein Data Bank (PDB). Starting from the macromolecular crystallographic information files (mmCIF) in the PDB archive, covalent bond records, which indicate the side chain modification of amino acid residue by a covalent binder, were collected and cleaned. Then, residue-binder adducts, which are products of chemical reactions between targeted residues and covalent binders, were recovered with the help of the Chemical Component Dictionary in PDB. Finally, several strategies were employed to curate the pre-reaction forms of covalent binders from the adducts. Our curated CovBinderInPDB database contains 7375 covalent modifications in which 2189 unique covalent binders target nine types of amino acid residues (Cys, Lys, Ser, Asp, Glu, His, Met, Thr, and Tyr) from 3555 complex structures of 1170 unique protein chains. This database would set a solid foundation for developing and benchmarking computational strategies for covalent modulator design and is freely accessible at https://yzhang.hpc.nyu.edu/CovBinderInPDB.

Figure 1.

Front page of CovBinderInPDB’s web portal.

Figure 2.

The lists have been truncated for clarity. (a) List of residue targets in the CovBinderInPDB. The counts of unique binders are shown in the bottom-right corner. (b) List of available warheads. The reaction patterns are marked. The red arrow indicates the target atom of the nucleophilic attack (by amino acid residue). The red cross indicates bond breakage in the reaction. The green-highlighted area indicates the leaving group. (c) List of available binders. These binders contain selected warheads and react with selected residues. (d) Record list.

Figure 3.

Lists have been truncated for clarity. (a) List of available warheads. The counts of unique binders are shown in the bottom-right corner. (b) List of residue targets in the CovBinderInPDB. (c) List of available binders. These binders contain selected warheads and react with selected residues. (c) Record list.

Figure 4.

The record page visualizes the covalent modification and provides relevant information.

Scheme 1.

Workflow to Curate Known Covalent Binders from the Protein Data Bank^{a a} (Number of RBAs is lower than the number of CBRs because the same RBA can be reconstructed based on different records. The number of covalent binders is different from the number of RBAs because the same binder can end up in different adducts together with different residues or different binders can drop different leaving groups and end up into identical adducts.)

Scheme 2.

Removed examples^{a a} (a) Selenium is not on the list of allowed element. (b) γO can be targeted and C cannot. (c) Residue Thr is in a nonpolymeric chain. In other words, it is not in a protein chain.

Scheme 3.

(a) 2D Projection of One Extracted Adduct from the 1PWC, Whose Covalent Record Is Presented in Table 1. The Underlined OG Represents the γ Oxygen Atom of the Serine Residue. All Other Displayed Atoms Belong to the Binder. Irrelevant Atoms in Serine Are Omitted in the Adduct for Simplicity. (b) Corresponding Reconstructed PFB. (c) Linking a Placeholder Atom Te to the Reconstructed PFB Yields the Recovered Adduct. d) Recovered Covalent Binder in its Pre-Reaction Form.

Scheme 4.

(a) 3D Projection of Another Extracted Adduct from PDB 3ROK. The Underlined OE2 Is from Glutamic Acid and All Other Displayed Atoms Are from the Binder. The Covalent Bond Record Shows That C1 and OE2 Are Bond-Forming Atoms. (b) Corresponding Reconstructed PFB. (c) Recovered Adduct. (d) Recovered Binder.

Scheme 5.

Characteristic Substructure Indicates the Warhead Is a Ketone Group.