CovalentInDB 2.0: an updated comprehensive database for structure-based and ligand-based covalent inhibitor design and screening

Abstract

The rational design of targeted covalent inhibitors (TCIs) has emerged as a powerful strategy in drug discovery, known for its ability to achieve strong binding affinity and prolonged target engagement. However, the development of covalent drugs is often challenged by the need to optimize both covalent warhead and non-covalent interactions, alongside the limitations of existing compound libraries. To address these challenges, we present CovalentInDB 2.0, an updated online database designed to support covalent drug discovery. This updated version includes 8303 inhibitors and 368 targets, supplemented by 3445 newly added cocrystal structures, providing detailed analyses of non-covalent interactions. Furthermore, we have employed an AI-based model to profile the ligandability of 144 864 cysteines across the human proteome. CovalentInDB 2.0 also features the largest covalent virtual screening library with 2 030 192 commercially available compounds and a natural product library with 105 901 molecules, crucial for covalent drug screening and discovery. To enhance the utility of these compounds, we performed structural similarity analysis and drug-likeness predictions. Additionally, a new user data upload feature enables efficient data contribution and continuous updates. CovalentInDB 2.0 is freely accessible at http://cadd.zju.edu.cn/cidb/.

Graphical Abstract

Figure 1.

(A) Structure of the ligand and covalent binding information within the cocrystal structure of the covalent inhibitor-target complex. (B) Non-covalent interactions between the ligand and receptor.

Figure 2.

(A) Acquisition of profiled cysteine ligandability data. (B) Ranking of ligandability for all flexible cysteines in a protein structure (2P2H). (C) Display of potential covalent binding sites and surrounding pharmacophore features in ‘Site View’ mode.

Figure 3.

(A) Browsing the two libraries by warhead type. (B) Structure, warhead, and ADMET properties of natural products or virtual screening compounds. (C) Compounds in the covalent virtual screening library with structures similar to the inhibitor CI002722.