Text
Drug Docking Studies with SARS-CoV-2
Anna Bachmann, Jennifer Muzyka
Department of Chemistry, Centre College, Danville, KY 40422
Introduction
SARS-CoV-2 Main Protease
Visualizing Docking Results
Computer-based docking has recently moved to the
forefront of drug discovery research as it allows
scientists to quickly and affordably understand how
small molecules bind and interact with proteins and
other biological structures. This technology allows
researchers to quantitatively evaluate the potential of
large numbers of ligands to act as therapeutic drugs,
which greatly narrows down the laboratory testing
required for further studies. SARS-CoV-2, the virus
responsible for the COVID-19 pandemic, emerged
early in 2020 as a large global threat and stimulated
the rapid response of scientists all over the world as
they searched for preventative and reactive
measures to hinder it.
SARS-CoV-2, a deadly coronavirus, works under the same functionality as most
other viruses. Upon entry into the body, a SARS-CoV-2 virus binds to an ACE2
receptor on the surface of cells mainly in the lungs using a spike protein. Upon
entry into the cell, the viral capsid hijacks host cell ribosomes to translate the
virus’s RNA into viral proteins, allowing for replication of the virus and its
subsequent spread throughout the body. Sixteen non-structural proteins are
synthesized from the virus via host cell machinery to assist in the seven-step
process of viral replication, making them attractive targets for inhibition. NSP5, also
known as the main protease, is responsible for cleaving much of the amino acid
sequence synthesized in the host cell into individual non-structural proteins crucial
for replication. The main protease has a cysteine-histidine residue in its active site
and can cleave glutamine-serine, glutamine-alanine, and glutamine-glycine peptide
bonds. If the main protease can be targeted in treatment, then replication of the
SARS-CoV-2 virus is massively disrupted, making it a focal point of drug design.
Although PyRx provides valuable quantitative binding results,
its imaging is not very accessible nor digestible. Chimera can
be used to visualize the docking results from PyRx. The
qualitative binding site interactions of the main protease with a
ligand can be clearly highlighted with colorful modifications
and affinity labeling that researchers can adjust to their liking.
Both subunits of main
protease in complex
with boceprevir.
PDB: 7BRP
LEFT: Superposition of
main protease in complex
with boceprevir (tan) and
unbound main protease
(blue), showing residue
interactions in yellow
between ligand (pink) and
main protease (tan).
PDB: 7BRP, 7BRO
RIGHT: Main protease
in complex with
boceprevir. Binding
site surface of main
protease is labeled by
hydrophobicity (blue is
polar, red is nonpolar).
PDB: 7BRP
SARS-CoV-2 virus. CDC.
Preliminary Docking Results
Transition from DOCK 6
to PyRx
This investigation into computer-aided drug design began
using the UCSF DOCK 6 program, which predicts binding
of small molecules using various algorithms. It quickly
became apparent that DOCK 6 was not very user-friendly
to chemists first getting started with molecular docking. A
more accessible program called PyRx was found with the
help of Dr. Muzyka. This program was much easier to
download, did not require a very deep understanding of
computer programming, and had a navigable interface that
gave more straightforward docking results. The PyRx
tutorials were easier to follow and could be accomplished
in terms of hours instead of days. A couple drawbacks of
PyRx is that it is less refined and accurate than DOCK, but
the results are satisfactory for the scope of our research.
Ideal docking results for viable drug targets will be at binding affinities of -9 and
lower. Because of the main protease’s ability to cleave Q-S/A/G links, peptide
analogs of similar structure are predicted to be suitable ligands. Thus far, the
ligands that have been docked in PyRx with the main protease have only yielded
binding affinities as low as -7.1. However, computations done by Dr. Toth’s
students are in progress that have already shown binding affinities as low as -9.5.
Conclusions and Future Work
Computer-based drug docking with the SARS-CoV-2 main
protease shows promise for identification of viable small
molecules for further study as anti-viral treatments.
Future plans include:
- Analyzing additional results from higher-level docking
calculations.
- Identifying other potential drug targets for SARSCoV-2 inhibition for further docking studies.
Acknowledgments
I would like to thank Centre College and its chemistry department for the opportunity to participate in
this research. I would also like to thank Dr. Toth for providing parallel docking calculations, as well as
Mason Saunders, Ben Hammond, and Sam Biggerstaff for their help with background information and
tutorials. Funding for this project is from Centre College.
References
Binding affinity: -9.4 kcal/mol
Binding affinities of the most
favorable conformation of various
ligands with the main protease.
Binding affinity: -9.5 kcal/mol
(ZINC5545321)
(ZINC5948917)
Yoshimoto, F. K. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the
Cause of COVID-19. Protein J. 2020, 39 (3), 198–216. https://doi.org/10.1007/s10930-020-09901-4.
Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H.
Analysis of Therapeutic Targets for SARS-CoV-2 and Discovery of Potential Drugs by Computational Methods. Acta Pharm.
Sin. B 2020, 10 (5), 766–788. https://doi.org/10.1016/j.apsb.2020.02.008.
https://pyrx.sourceforge.io
https://www.cgl.ucsf.edu/chimera/
Anna Bachmann, Jennifer Muzyka
Department of Chemistry, Centre College, Danville, KY 40422
Introduction
SARS-CoV-2 Main Protease
Visualizing Docking Results
Computer-based docking has recently moved to the
forefront of drug discovery research as it allows
scientists to quickly and affordably understand how
small molecules bind and interact with proteins and
other biological structures. This technology allows
researchers to quantitatively evaluate the potential of
large numbers of ligands to act as therapeutic drugs,
which greatly narrows down the laboratory testing
required for further studies. SARS-CoV-2, the virus
responsible for the COVID-19 pandemic, emerged
early in 2020 as a large global threat and stimulated
the rapid response of scientists all over the world as
they searched for preventative and reactive
measures to hinder it.
SARS-CoV-2, a deadly coronavirus, works under the same functionality as most
other viruses. Upon entry into the body, a SARS-CoV-2 virus binds to an ACE2
receptor on the surface of cells mainly in the lungs using a spike protein. Upon
entry into the cell, the viral capsid hijacks host cell ribosomes to translate the
virus’s RNA into viral proteins, allowing for replication of the virus and its
subsequent spread throughout the body. Sixteen non-structural proteins are
synthesized from the virus via host cell machinery to assist in the seven-step
process of viral replication, making them attractive targets for inhibition. NSP5, also
known as the main protease, is responsible for cleaving much of the amino acid
sequence synthesized in the host cell into individual non-structural proteins crucial
for replication. The main protease has a cysteine-histidine residue in its active site
and can cleave glutamine-serine, glutamine-alanine, and glutamine-glycine peptide
bonds. If the main protease can be targeted in treatment, then replication of the
SARS-CoV-2 virus is massively disrupted, making it a focal point of drug design.
Although PyRx provides valuable quantitative binding results,
its imaging is not very accessible nor digestible. Chimera can
be used to visualize the docking results from PyRx. The
qualitative binding site interactions of the main protease with a
ligand can be clearly highlighted with colorful modifications
and affinity labeling that researchers can adjust to their liking.
Both subunits of main
protease in complex
with boceprevir.
PDB: 7BRP
LEFT: Superposition of
main protease in complex
with boceprevir (tan) and
unbound main protease
(blue), showing residue
interactions in yellow
between ligand (pink) and
main protease (tan).
PDB: 7BRP, 7BRO
RIGHT: Main protease
in complex with
boceprevir. Binding
site surface of main
protease is labeled by
hydrophobicity (blue is
polar, red is nonpolar).
PDB: 7BRP
SARS-CoV-2 virus. CDC.
Preliminary Docking Results
Transition from DOCK 6
to PyRx
This investigation into computer-aided drug design began
using the UCSF DOCK 6 program, which predicts binding
of small molecules using various algorithms. It quickly
became apparent that DOCK 6 was not very user-friendly
to chemists first getting started with molecular docking. A
more accessible program called PyRx was found with the
help of Dr. Muzyka. This program was much easier to
download, did not require a very deep understanding of
computer programming, and had a navigable interface that
gave more straightforward docking results. The PyRx
tutorials were easier to follow and could be accomplished
in terms of hours instead of days. A couple drawbacks of
PyRx is that it is less refined and accurate than DOCK, but
the results are satisfactory for the scope of our research.
Ideal docking results for viable drug targets will be at binding affinities of -9 and
lower. Because of the main protease’s ability to cleave Q-S/A/G links, peptide
analogs of similar structure are predicted to be suitable ligands. Thus far, the
ligands that have been docked in PyRx with the main protease have only yielded
binding affinities as low as -7.1. However, computations done by Dr. Toth’s
students are in progress that have already shown binding affinities as low as -9.5.
Conclusions and Future Work
Computer-based drug docking with the SARS-CoV-2 main
protease shows promise for identification of viable small
molecules for further study as anti-viral treatments.
Future plans include:
- Analyzing additional results from higher-level docking
calculations.
- Identifying other potential drug targets for SARSCoV-2 inhibition for further docking studies.
Acknowledgments
I would like to thank Centre College and its chemistry department for the opportunity to participate in
this research. I would also like to thank Dr. Toth for providing parallel docking calculations, as well as
Mason Saunders, Ben Hammond, and Sam Biggerstaff for their help with background information and
tutorials. Funding for this project is from Centre College.
References
Binding affinity: -9.4 kcal/mol
Binding affinities of the most
favorable conformation of various
ligands with the main protease.
Binding affinity: -9.5 kcal/mol
(ZINC5545321)
(ZINC5948917)
Yoshimoto, F. K. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the
Cause of COVID-19. Protein J. 2020, 39 (3), 198–216. https://doi.org/10.1007/s10930-020-09901-4.
Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H.
Analysis of Therapeutic Targets for SARS-CoV-2 and Discovery of Potential Drugs by Computational Methods. Acta Pharm.
Sin. B 2020, 10 (5), 766–788. https://doi.org/10.1016/j.apsb.2020.02.008.
https://pyrx.sourceforge.io
https://www.cgl.ucsf.edu/chimera/