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Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites

Journal Article · · Journal of Chemical Information and Modeling
 [1];  [1];  [2];  [3];  [2];  [4];  [5];  [5];  [1];  [6];  [6];  [7];  [8];  [9];  [10];  [11];  [12];  [1]
  1. Univ. College London (United Kingdom). School of Pharmacy
  2. Aligarh Muslim University, Aligarh, Uttar Pradesh (India). Dept. of Biochemistry
  3. Aligarh Muslim University, Aligarh, Uttar Pradesh (India). Dept. of Zoology
  4. Herricks High School, New Hyde Park, NY (United States)
  5. Univ. of Karachi (Pakistan). International Centre of Chemical and Biological Sciences, H.E.J. Research Institute of Chemistry, Third World Center for Science and Technology
  6. Brunel Univ., Uxbridge (United Kingdom). Dept. of Computer Science
  7. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Computational Sciences
  8. Argonne National Lab. (ANL), Argonne, IL (United States). Data Science and Learning Division
  9. Argonne National Lab. (ANL), Argonne, IL (United States). Data Science and Learning Division; Univ. of Chicago (United States). Consortium for Advanced Science and Engineering
  10. Univ. of Huddersfield (United Kingdom). Dept. of Bioscience
  11. Univ. of Edinburgh, Scotland (United Kingdom). EaStCHEM School of Chemistry
  12. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Computer Sciences and Engineering Division
+ Show Author Affiliations
β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR) (SC-21)
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1807238
Journal Information:
Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 6 Vol. 61; ISSN 1549-9596
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English

References (78)

Improving efficiency of large time-scale molecular dynamics simulations of hydrogen-rich systems journal June 1999
Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features journal December 1983
Rapid Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease by Deep Docking of 1.3 Billion Compounds journal March 2020
Learning generative models for protein fold families
  • Balakrishnan, Sivaraman; Kamisetty, Hetunandan; Carbonell, Jaime G.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 79, Issue 4 https://doi.org/10.1002/prot.22934
journal January 2011
Coronaviruses: An Overview of Their Replication and Pathogenesis book January 2015
Activation and maturation of SARS-CoV main protease journal April 2011
VMD: Visual molecular dynamics journal February 1996
Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics journal September 2020
The SARS-CoV-2 main protease as drug target journal September 2020
Lower respiratory tract infection in the community: associations between viral aetiology and illness course journal January 2021
Robust Perron cluster analysis in conformation dynamics journal March 2005
Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease journal June 2020
SARS-CoV-2 Main Protease: A Molecular Dynamics Study journal August 2020
Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19 journal December 2020
PlayMolecule ProteinPrepare: A Web Application for Protein Preparation for Molecular Dynamics Simulations journal June 2017
BiKi Life Sciences: A New Suite for Molecular Dynamics and Related Methods in Drug Discovery journal January 2018
What Markov State Models Can and Cannot Do: Correlation versus Path-Based Observables in Protein-Folding Models journal April 2021
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB journal July 2015
PyEMMA 2: A Software Package for Estimation, Validation, and Analysis of Markov Models journal October 2015
HTMD: High-Throughput Molecular Dynamics for Molecular Discovery journal March 2016
Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities journal November 2020
Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2 journal October 2020
Uncovering Flexible Active Site Conformations of SARS-CoV-2 3CL Proteases through Protease Pharmacophore Clusters and COVID-19 Drug Repurposing journal December 2020
Probing the Dynamic Structure–Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory journal November 2020
Markov State Models Provide Insights into Dynamic Modulation of Protein Function journal January 2015
Evidence for Substrate Binding-Induced Zwitterion Formation in the Catalytic Cys-His Dyad of the SARS-CoV Main Protease journal September 2014
Role of the Ω-Loop in the Activity, Substrate Specificity, and Structure of Class A β-Lactamase † , ‡ journal March 1998
Improvements in Markov State Model Construction Reveal Many Non-Native Interactions in the Folding of NTL9 journal March 2013
Structure and Dynamics of the TIP3P, SPC, and SPC/E Water Models at 298 K journal November 2001
Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models journal July 2015
SARS and MERS: recent insights into emerging coronaviruses journal June 2016
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease journal October 2020
Coronavirus biology and replication: implications for SARS-CoV-2 journal October 2020
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors journal April 2020
The coding capacity of SARS-CoV-2 journal September 2020
SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging journal October 2020
Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur journal May 2020
Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A journal January 2020
Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 M pro by QM/MM computational methods journal January 2020
Mechanism of inhibition of SARS-CoV-2 M pro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity journal January 2021
Structure-based enzyme engineering improves donor-substrate recognition of Arabidopsis thaliana glycosyltransferases journal August 2020
Update on Human Rhinovirus and Coronavirus Infections journal August 2016
A smooth particle mesh Ewald method journal November 1995
Identification of slow molecular order parameters for Markov model construction journal July 2013
Markov Models of Molecular Kinetics journal November 2019
Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations journal June 2011
Assessing the utility of coevolution-based residue-residue contact predictions in a sequence- and structure-rich era journal September 2013
Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning journal February 2019
Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease. journal April 1967
Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro) journal August 2015
Critical Assessment of Important Regions in the Subunit Association and Catalytic Action of the Severe Acute Respiratory Syndrome Coronavirus Main Protease journal April 2005
Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes journal April 2020
Forty years with coronaviruses journal March 2020
Detection of the New Human Coronavirus HKU1: A Report of 6 Cases journal March 2006
The Protein Imager: a full-featured online molecular viewer interface with server-side HQ-rendering capabilities journal January 2020
Computational analysis of dynamic allostery and control in the SARS-CoV-2 main protease journal January 2021
Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets posted_content April 2020
Structure of the SARS coronavirus main proteinase as an active C 2 crystallographic dimer journal October 2005
DeepDriveMD: Deep-Learning Driven Adaptive Molecular Simulations for Protein Folding conference November 2019
Towards Native Execution of Deep Learning on a Leadership-Class HPC System conference May 2019
XSEDE: Accelerating Scientific Discovery journal September 2014
From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design journal August 2014
The catalysis of the SARS 3C-like protease is under extensive regulation by its extra domain journal March 2006
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors journal March 2020
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease journal April 2020
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease journal April 2021
Discovery of Seven Novel Mammalian and Avian Coronaviruses in the Genus Deltacoronavirus Supports Bat Coronaviruses as the Gene Source of Alphacoronavirus and Betacoronavirus and Avian Coronaviruses as the Gene Source of Gammacoronavirus and Deltacoronavirus journal January 2012
Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus journal December 2005
Deep clustering of protein folding simulations journal December 2018
HH-suite3 for fast remote homology detection and deep protein annotation journal September 2019
From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses journal August 2020
Characterization of accessory genes in coronavirus genomes journal August 2020
Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates journal January 2020
Maximum Allowed Solvent Accessibilites of Residues in Proteins journal November 2013
A New Virus Isolated from the Human Respiratory Tract. journal January 1966
Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19 journal December 2020
Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulations journal July 2020
Human Coronaviruses: Insights into Environmental Resistance and Its Influence on the Development of New Antiseptic Strategies journal November 2012

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Conformation
Ligands
Peptides and proteins
SARS-CoV
Screening assays