Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor

Journal Article · · ACS Pharmacology & Translational Science
 [1];  [1];  [2];  [3];  [1];  [1];  [4];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [4];  [1];  [1];  [1]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Merck, Rahway, NJ (United States)
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); New England Biolabs, Ipswich, MA (United States)
  4. University of L'Aquila (Italy)
+ Show Author Affiliations
Inhibition of the SARS-CoV-2 main protease (Mpro) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of Mpro. Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC50 values around 1 μM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein–inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for Mpro inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR)
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1864414
Journal Information:
ACS Pharmacology & Translational Science, Journal Name: ACS Pharmacology & Translational Science Journal Issue: 4 Vol. 5; ISSN 2575-9108
Publisher:
ACS PublicationsCopyright Statement
Country of Publication:
United States
Language:
English

References (64)

Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation journal October 2002
Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model journal April 2003
Development and testing of a general amber force field journal January 2004
UCSF Chimera?A visualization system for exploratory research and analysis journal January 2004
Effect of the damping function in dispersion corrected density functional theory journal March 2011
Using Dali for Protein Structure Comparison book January 2020
VMD: Visual molecular dynamics journal February 1996
Self-consistent molecular Hartree—Fock—Slater calculations I. The computational procedure journal September 1973
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings journal January 1997
A deliberate approach to screening for initial crystallization conditions of biological macromolecules journal April 2003
From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses journal October 2013
Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate journal June 2004
Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors journal June 2005
Water, water, everywhere… It's time to stop and think journal July 2016
The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020 journal November 2020
Malleability of the SARS-CoV-2 3CL Mpro Active-Site Cavity Facilitates Binding of Clinical Antivirals journal December 2020
NMR-based screening in drug discovery journal August 1999
The Halogen Bond journal January 2016
Computer Modeling of Halogen Bonds and Other σ-Hole Interactions journal February 2016
Virtual Screening: Is Bigger Always Better? Or Can Small Be Beautiful? journal May 2020
Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19 journal December 2020
High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor journal November 2021
ff19SB: Amino-Acid-Specific Protein Backbone Parameters Trained against Quantum Mechanics Energy Surfaces in Solution journal November 2019
Perspectives on SARS-CoV-2 Main Protease Inhibitors journal November 2021
Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CL pro ) journal August 2021
Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease journal October 2021
The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug Discovery journal May 2017
Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design journal April 2021
Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations journal February 2021
Quantum Chemical Studies of Mechanisms for Metalloenzymes journal January 2014
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K a Predictions journal December 2010
Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K a Values journal June 2011
Standard Free Energy of Releasing a Localized Water Molecule from the Binding Pockets of Proteins:  Double-Decoupling Method journal June 2004
Classification of Water Molecules in Protein Binding Sites journal March 2007
Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses journal February 2022
Molecular Properties That Influence the Oral Bioavailability of Drug Candidates journal June 2002
Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-x L from NMR and Parallel Synthesis journal December 2005
Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology journal January 2013
A tale of two antiviral targets — and the COVID-19 drugs that bind them journal December 2021
Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography journal June 2020
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors journal April 2020
Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease journal January 2021
Accurate Coulomb-fitting basis sets for H to Rn journal January 2006
A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu journal April 2010
On some approximations in applications of X α theory journal October 1979
Density functional calculations of molecular bond energies journal April 1986
Fully optimized contracted Gaussian basis sets for atoms Li to Kr journal August 1992
Density‐functional thermochemistry. III. The role of exact exchange journal April 1993
Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease journal May 2020
Density-functional approximation for the correlation energy of the inhomogeneous electron gas journal June 1986
Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density journal January 1988
Phaser crystallographic software journal July 2007
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Room-temperature neutron and X-ray data collection of 3CL M pro from SARS-CoV-2 journal September 2020
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors journal March 2020
SARS-CoV-2 M pro inhibitors with antiviral activity in a transgenic mouse model journal February 2021
An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19 journal December 2021
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays journal April 1999
One molecular fingerprint to rule them all: drugs, biomolecules, and the metabolome journal June 2020
Definition of the halogen bond (IUPAC Recommendations 2013) journal July 2013
OpenMM 7: Rapid development of high performance algorithms for molecular dynamics journal July 2017
The interplay of SARS-CoV-2 evolution and constraints imposed by the structure and functionality of its proteins journal July 2021

Similar Records

A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors**
Journal Article · Sun Dec 06 19:00:00 EST 2020 · ChemMedChem · OSTI ID:1837373

Related Subjects

60 APPLIED LIFE SCIENCES
SARS-CoV-2
antiviral therapeutics
drug discovery
hit expansion
main protease inhibitor