An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor

DOI: 10.1016/j.chembiol.2021.05.018

Authors: Daniel Zaidman (Weizmann Institute of Science) , Paul Gehrtz (Weizmann Institute of Science) , Mihajlo Filep (Weizmann Institute of Science) , Daren Fearon (Diamond Light Source) , Ronen Gabizon (Weizmann Institute of Science) , Alice Douangamath (Diamond Light Source) , Jaime Prilusky (Weizmann Institute of Science) , Shirly Duberstein (Weizmann Institute of Science) , Galit Cohen (Weizmann Institute of Science) , C. David Owen (Diamond Light Source; Research Complex at Harwell) , Efrat Resnick (Weizmann Institute of Science) , Claire Strain-Damerell (Diamond Light Source; Research Complex at Harwell) , Petra Lukacik (Diamond Light Source; Research Complex at Harwell) , Haim Barr (Weizmann Institute of Science) , Martin A. Walsh (Diamond Light Source; Research Complex at Harwell) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford; University of Johannesburg) , Nir London (Weizmann Institute of Science)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology , VOL 63

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 18145 , 27963

Abstract: 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.

Journal Keywords: irreversible inhibitors; covalent inhibitors; covalent docking; computer-aided drug discovery; DOCKovalent; COVID-19; SARS-CoV-2; Mpro

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/06/2021 09:25

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Information & Communication Technologies Chemistry Structural biology Organic Chemistry Data processing Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)