Covalent Inhibitors are an increasingly important class of therapeutic agents.
A computational pipeline has been described by the London lab to predict suggest covalent analogs of non-covalent ligands DOI.
Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In a prospective evaluation, five out of nine predicted covalent kinase inhibitors showed half-maximal inhibitory concentration (IC50) values between 155 nM and 4.5 μM. Application against an existing SARS-CoV Mpro reversible inhibitor led to an acrylamide inhibitor series with low micromolar IC50 values against SARS-CoV-2 Mpro. The docking was validated by 12 co-crystal structures. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.
RDKit was used for 2D molecular handling, conformation generation and RMSD calculation. RDKit: Open-source cheminformatics; version 2018.09.3; RDKit.org. Marvin was used in the process of preparing the molecules for docking, Marvin 17.21.0, ChemAxon (https://www.chemaxon.com). OpenBabel (http:// openbabel.org/wiki/Main_Page) was used to switch between molecular file formats. DOCKovalent (London et al., 2014) was used for virtual covalent docking. The Covalentizer code is available at https://github.com/LondonLab/Covalentizer.
I've written a page in the Drug Discovery Resources on covalent inhibitors.
This publication suggests this area is going to become more important "An activity-guided map of electrophile-cysteine interactions in primary human immune cells" https://www.biorxiv.org/content/10.1101/808113v1.
Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology.
I've updated the covalent inhibitors page to include details of two covalent fragment libraries that have been used in fragment screening.
I've made a few additions and updated to the Drug Discovery Resources pages. In particular I've updated the covalent inhibitors page and added additional examples to the molecular interactions page. I've also started updating the ADME section and added a page on half-life and how it might be modulated.