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Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing

Journal Article · · Structure
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  1. Bahcesehir University, Istanbul (Turkey); SLAC
  2. Koc University, Istanbul (Turkey)
  3. Bahcesehir University, Istanbul (Turkey)
  4. Bahcesehir University, Istanbul (Turkey); Gebze Technical University, Kocaeli (Turkey)
  5. Bahcesehir University, Istanbul (Turkey); Istanbul Technical University (Turkey)
  6. Bahcesehir University, Istanbul (Turkey); Mersin University (Turkey)
  7. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
  8. Arizona State Univ., Tempe, AZ (United States)
  9. SLAC National Accelerator Lab., Menlo Park, CA (United States). Photon Ultrafast Laser Science and Engineering Inst. (PULSE)
  10. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
  11. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS); Stanford Univ., CA (United States)
  12. State Univ. of New York at Buffalo, NY (United States)
  13. Koc University, Istanbul (Turkey); SLAC National Accelerator Lab., Menlo Park, CA (United States). Photon Ultrafast Laser Science and Engineering Inst. (PULSE)
+ Show Author Affiliations
The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.
Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
Bahcesehir University (BAU) Scientific Research Projects (BAP); National Science Foundation (NSF); Scientific and Technological Research Council of Turkey (TUBITAK); USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1819309
Report Number(s):
SLAC-PUB--17616
Journal Information:
Structure, Journal Name: Structure Journal Issue: 12 Vol. 29; ISSN 0969-2126
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

References (97)

Emerging coronaviruses: Genome structure, replication, and pathogenesis journal February 2020
Rapid Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease by Deep Docking of 1.3 Billion Compounds journal March 2020
A hierarchical approach to all-atom protein loop prediction journal March 2004
Very fast prediction and rationalization of pKa values for protein-ligand complexes journal May 2008
Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations journal November 1991
Repurposed GI Drugs in the Treatment of COVID-19 journal June 2020
Epik: a software program for pK a prediction and protonation state generation for drug-like molecules journal September 2007
Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments journal March 2013
SARS-CoV-2 and Male Infertility: Possible Multifaceted Pathology journal July 2020
SARS-CoV-2 renal tropism associates with acute kidney injury journal August 2020
Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics journal September 2020
Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia journal July 2020
Serial femtosecond crystallography: A revolution in structural biology journal July 2016
Crystal structure of SARS-CoV-2 papain-like protease journal January 2021
Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro journal January 2008
The SARS-CoV-2 main protease as drug target journal September 2020
Domain-Opening and Dynamic Coupling in the α-Subunit of Heterotrimeric G Proteins journal July 2013
The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China journal May 2020
Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model journal January 2020
Predictive methods in drug repurposing: gold mine or just a bigger haystack? journal June 2013
Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections journal August 2020
In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing journal September 2020
A Bright Future for Serial Femtosecond Crystallography with XFELs journal September 2017
Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study journal April 2020
SARS-CoV-2 Main Protease: A Molecular Dynamics Study journal August 2020
OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins journal December 2015
An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy journal February 2016
Comprehensive Insights into the Catalytic Mechanism of Middle East Respiratory Syndrome 3C-Like Protease and Severe Acute Respiratory Syndrome 3C-Like Protease journal April 2020
Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy journal May 2020
Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2 journal October 2020
Normal Mode Analysis of Biomolecular Structures: Functional Mechanisms of Membrane Proteins journal March 2010
The missing term in effective pair potentials journal November 1987
Glide:  A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy journal March 2004
Glide:  A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening journal March 2004
Novel Procedure for Modeling Ligand/Receptor Induced Fit Effects journal January 2006
Extra Precision Glide:  Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand Complexes journal October 2006
US FDA approves new class of HIV therapeutics journal May 2003
Concentric-flow electrokinetic injector enables serial crystallography of ribosome and photosystem II journal November 2015
Drug repurposing: progress, challenges and recommendations journal October 2018
Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 journal March 2020
Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease journal June 2020
Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography journal June 2020
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease journal October 2020
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors journal April 2020
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing journal April 2020
The proximal origin of SARS-CoV-2 journal March 2020
Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2 journal February 2021
Remdesivir for the Treatment of Covid-19 — Final Report journal November 2020
A unified formulation of the constant temperature molecular dynamics methods journal July 1984
A smooth particle mesh Ewald method journal November 1995
Performance of ePix10K, a high dynamic range, gain auto-ranging pixel detector for FELs
  • Blaj, G.; Dragone, A.; Kenney, C. J.
  • PROCEEDINGS OF THE 13TH INTERNATIONAL CONFERENCE ON SYNCHROTRON RADIATION INSTRUMENTATION – SRI2018, AIP Conference Proceedings https://doi.org/10.1063/1.5084693
conference January 2019
Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19 journal April 2020
Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2′-O-ribose methyltransferase journal April 2020
Bio3d: an R package for the comparative analysis of protein structures journal August 2006
Virus-encoded proteinases and proteolytic processing in the Nidovirales journal April 2000
Mechanisms and enzymes involved in SARS coronavirus genome expression journal September 2003
Canonical dynamics: Equilibrium phase-space distributions journal March 1985
Phaser crystallographic software journal July 2007
CrystFEL : a software suite for snapshot serial crystallography journal March 2012
Indexing in single-crystal diffractometry with an obstinate list of reflections journal April 1992
Coot model-building tools for molecular graphics journal November 2004
XDS journal January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Overview of the CCP 4 suite and current developments journal March 2011
Nanoflow electrospinning serial femtosecond crystallography journal October 2012
Autoindexing diffraction images with iMosflm journal June 2013
Cheetah : software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data journal May 2014
Linac Coherent Light Source data analysis using psana journal March 2016
Recent developments in CrystFEL journal March 2016
OnDA : online data analysis and feedback for serial X-ray imaging journal May 2016
The Macromolecular Femtosecond Crystallography Instrument at the Linac Coherent Light Source journal February 2019
The ePix10k 2-megapixel hard X-ray detector at LCLS journal April 2020
XGANDALF – extended gradient descent algorithm for lattice finding journal August 2019
Processing serial crystallography data with CrystFEL : a step-by-step guide journal January 2019
Drugs for hyperlipidaemia may slow down the progression of hearing loss in the elderly: A drug repurposing study journal November 2018
Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease journal August 2020
Linking Crystallographic Model and Data Quality journal May 2012
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
3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV–infected mice journal August 2020
Without Its N-Finger, the Main Protease of Severe Acute Respiratory Syndrome Coronavirus Can Form a Novel Dimer through Its C-Terminal Domain journal May 2008
Cultivation of a Novel Type of Common-cold Virus in Organ Cultures journal June 1965
Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: a multi-center observational study journal January 2021
A review of computational drug repositioning: strategies, approaches, opportunities, challenges, and directions journal July 2020
Data systems for the Linac coherent light source journal January 2017
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
iDrug: Integration of drug repositioning and drug-target prediction via cross-network embedding journal July 2020
Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease journal May 2014
Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury journal March 2020
Antiviral Drug Targets of Single-Stranded RNA Viruses Causing Chronic Human Diseases journal January 2020
Global Surveillance, National Surveillance, and SARS journal February 2004
The COVID-19 Cytokine Storm; What We Know So Far journal June 2020
Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach journal July 2020
Human Immunodeficiency Virus Proteins Mimic Human T Cell Receptors Inducing Cross-Reactive Antibodies journal October 2017
Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for Novel Coronavirus Disease 2019 (COVID-19) journal March 2020
SARS-CoV-2 strategically mimics proteolytic activation of human ENaC journal May 2020
Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov journal January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
SARS-CoV-2
SFX
ambient temperature
drug repurposing
main protease