Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

Experimental Validation ◽

Antiviral Agents ◽

Spike Protein ◽

Binding Affinities ◽

Converting Enzyme ◽

Lead Compounds ◽

Virtual Screening Approach

E2/21-12-2020<br><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them in clinical trials - were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the correspond-ing binding affinities of thirteen such antiretroviral com-pounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2. <br><br><div><br></div><div>E1/24-08-2020</div><br>In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>lopinavir showed excellent results – binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.<br> </div><div><br></div>

Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

10.26434/chemrxiv.12857678.v2 ◽

2020 ◽

Author(s):

Konstantinos Kalamatianos

Keyword(s):

Clinical Trials ◽

Experimental Validation ◽

Antiviral Agents ◽

Spike Protein ◽

Binding Affinities ◽

Converting Enzyme ◽

Lead Compounds ◽

Virtual Screening Approach

E2/21-12-2020<br><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them in clinical trials - were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the correspond-ing binding affinities of thirteen such antiretroviral com-pounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2. <br><br><div><br></div><div>E1/24-08-2020</div><br>In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>lopinavir showed excellent results – binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.<br> </div><div><br></div>

Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

10.26434/chemrxiv.12857678.v3 ◽

2021 ◽

Author(s):

Konstantinos Kalamatianos

Keyword(s):

Clinical Trials ◽

Experimental Validation ◽

Antiviral Agents ◽

Spike Protein ◽

Binding Affinities ◽

Converting Enzyme ◽

Lead Compounds ◽

Virtual Screening Approach

<div>E3/03-03-2021<br></div><div>Molecular Dynamics Simulation has been added to E2/21-12-2020<br></div><div><br></div><div><br></div><div><br></div><div><br></div><div>E2/21-12-2020</div><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them in clinical trials - were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the correspond-ing binding affinities of thirteen such antiretroviral com-pounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2. <br><br><div><br></div><div>E1/24-08-2020</div><br>In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>lopinavir showed excellent results – binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.<br> </div><div><br></div>

Computational drug repurposing strategy predicted peptide-based drugs that can potentially inhibit the interaction of SARS-CoV-2 spike protein with its target (humanACE2)

PLoS ONE ◽

10.1371/journal.pone.0245258 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245258

Author(s):

Samuel Egieyeh ◽

Elizabeth Egieyeh ◽

Sarel Malan ◽

Alan Christofells ◽

Burtram Fielding

Keyword(s):

Protein Interaction ◽

Drug Repurposing ◽

Spike Protein ◽

Converting Enzyme ◽

Peptide Drugs ◽

Protein Protein Interaction ◽

Potential Inhibitors

Drug repurposing for COVID-19 has several potential benefits including shorter development time, reduced costs and regulatory support for faster time to market for treatment that can alleviate the current pandemic. The current study used molecular docking, molecular dynamics and protein-protein interaction simulations to predict drugs from the Drug Bank that can bind to the SARS-CoV-2 spike protein interacting surface on the human angiotensin-converting enzyme 2 (hACE2) receptor. The study predicted a number of peptide-based drugs, including Sar9 Met (O2)11-Substance P and BV2, that might bind sufficiently to the hACE2 receptor to modulate the protein-protein interaction required for infection by the SARS-CoV-2 virus. Such drugs could be validated in vitro or in vivo as potential inhibitors of the interaction of SARS-CoV-2 spike protein with the human angiotensin-converting enzyme 2 (hACE2) in the airway. Exploration of the proposed and current pharmacological indications of the peptide drugs predicted as potential inhibitors of the interaction between the spike protein and hACE2 receptor revealed that some of the predicted peptide drugs have been investigated for the treatment of acute respiratory distress syndrome (ARDS), viral infection, inflammation and angioedema, and to stimulate the immune system, and potentiate antiviral agents against influenza virus. Furthermore, these predicted drug hits may be used as a basis to design new peptide or peptidomimetic drugs with better affinity and specificity for the hACE2 receptor that may prevent interaction between SARS-CoV-2 spike protein and hACE2 that is prerequisite to the infection by the SARS-CoV-2 virus.

Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

10.33774/chemrxiv-2021-v0b70-v4 ◽

2021 ◽

Author(s):

Konstantinos Kalamatianos

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Spike Protein ◽

Converting Enzyme ◽

In Silico Screening ◽

Angiotensin Converting Enzyme 2

Testing of natural products in clinical trials targeting the SARS-CoV-2 (Covid-19) viral spike protein-angiotensin converting enzyme-2 (ACE2) interaction

Biochemical Pharmacology ◽

10.1016/j.bcp.2020.114123 ◽

2020 ◽

Vol 178 ◽

pp. 114123 ◽

Cited By ~ 5

Author(s):

Gary Williamson ◽

Asimina Kerimi

Keyword(s):

Clinical Trials ◽

Natural Products ◽

Spike Protein ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2

Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

10.33774/chemrxiv-2021-v0b70-v5 ◽

2021 ◽

Author(s):

Konstantinos Kalamatianos

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Spike Protein ◽

Converting Enzyme ◽

In Silico Screening ◽

Angiotensin Converting Enzyme 2

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

10.26434/chemrxiv.12186624.v3 ◽

2020 ◽

Author(s):

Cristina Garcia-Iriepa ◽

Cecilia Hognon ◽

Antonio Francés-Monerris ◽

Isabel Iriepa ◽

Tom Miclot ◽

...

Keyword(s):

Molecular Mechanisms ◽

Molecular Design ◽

Binding Free Energy ◽

Transmembrane Protein ◽

Spike Protein ◽

Converting Enzyme ◽

Rational Molecular Design ◽

Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>