Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding

DOI: 10.1039/D1SC03628A

Authors: H. T. Henry Chan (University of Oxford) , Marc A. Moesser (University of Oxford) , Rebecca K. Walters (University of Bristol) , Tika R. Malla (University of Oxford) , Rebecca M. Twidale (University of Bristol) , Tobias John (University of Oxford) , Helen M. Deeks (University of Bristol) , Tristan Johnston-Wood (University of Oxford) , Victor Mikhailov (University of Oxford) , Richard B. Sessions (University of Bristol) , William Dawson (RIKEN Center for Computational Science) , Eidarus Salah (University of Oxford) , Petra Lukacik (Diamond Light Source; Research Complex at Harwell) , Claire Strain-Damerell (Diamond Light Source; Research Complex at Harwell,) , C. David Owen (Diamond Light Source; Research Complex at Harwell) , Takahito Nakajima (RIKEN Center for Computational Science) , Katarzyna Świderek (Universitat Jaume I) , Alessio Lodola (University of Parma) , Vicent Moliner (Universitat Jaume I) , David R. Glowacki (University of Bristol) , James Spencer (University of Bristol) , Martin A. Walsh (Diamond Light Source; Research Complex at Harwell) , Christopher J. Schofield (University of Oxford) , Luigi Genovese (Univ. Grenoble Alpes, CEA, IRIG-MEM-L_Sim) , Deborah K. Shoemark (University of Bristol) , Adrian J. Mulholland (University of Bristol) , Fernanda Duarte (University of Oxford) , Garrett M. Morris (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 12 , PAGES 13686 - 13703

State: Published (Approved)
Published: October 2021

Abstract: The main protease (Mpro) of SARS-CoV-2 is central to viral maturation and is a promising drug target, but little is known about structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of biomolecular simulation techniques, including automated docking, molecular dynamics (MD) and interactive MD in virtual reality, QM/MM, and linear-scaling DFT, to investigate the molecular features underlying recognition of the natural Mpro substrates. We extensively analysed the subsite interactions of modelled 11-residue cleavage site peptides, crystallographic ligands, and docked COVID Moonshot-designed covalent inhibitors. Our modelling studies reveal remarkable consistency in the hydrogen bonding patterns of the natural Mpro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular plasticity at the S2 site. Building on our initial Mpro-substrate models, we used predictive saturation variation scanning (PreSaVS) to design peptides with improved affinity. Non-denaturing mass spectrometry and other biophysical analyses confirm these new and effective ‘peptibitors’ inhibit Mpro competitively. Our combined results provide new insights and highlight opportunities for the development of Mpro inhibitors as anti-COVID-19 drugs.

Diamond Keywords: COVID-19; Viruses; Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: NONE-No attached Diamond beamline

Added On: 15/11/2021 13:59

Documents:
d1sc03628a.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening