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