Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations
SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. The Omicron XBB subvariant, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (human Angiotensin-Converting Enzyme 2). Here we utilized multiligand...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-08-01
|
| Series: | Bioengineering |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2306-5354/10/8/961 |
| _version_ | 1797585492756135936 |
|---|---|
| author | Saleem Iqbal Sheng-Xiang Lin |
| author_facet | Saleem Iqbal Sheng-Xiang Lin |
| author_sort | Saleem Iqbal |
| collection | DOAJ |
| description | SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. The Omicron XBB subvariant, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (human Angiotensin-Converting Enzyme 2). Here we utilized multiligand virtual screening to identify small molecule inhibitors for their efficacy against SARS-CoV-2 virus using QPLD, pseudovirus ACE2 Inhibition -Time Resolved Forster/Fluorescence energy transfer (TR-FRET) Assay Screening, and Molecular Dynamics simulations (MDS). Three hundred and fifty thousand compounds were screened against the macrodomain of the nonstructural protein 3 of SARS-CoV-2. Using TR-FRET Assay, we filtered out two of 10 compounds that had no reported activity in in vitro screen against Spike S1: ACE2 binding assay. The percentage inhibition at 30 µM was found to be 79% for “Compound F1877-0839” and 69% for “Compound F0470-0003”. This first of its kind study identified “FILLY” pocket in macrodomains. Our 200 ns MDS revealed stable binding poses of both leads. They can be used for further development of preclinical candidates. |
| first_indexed | 2024-03-11T00:06:54Z |
| format | Article |
| id | doaj.art-ce09d93eb5e04b59aa9e3e2ca5a4edb3 |
| institution | Directory Open Access Journal |
| issn | 2306-5354 |
| language | English |
| last_indexed | 2024-03-11T00:06:54Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Bioengineering |
| spelling | doaj.art-ce09d93eb5e04b59aa9e3e2ca5a4edb32023-11-19T00:18:25ZengMDPI AGBioengineering2306-53542023-08-0110896110.3390/bioengineering10080961Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy CalculationsSaleem Iqbal0Sheng-Xiang Lin1Axe Molecular Endocrinology and Nephrology, CHU Research Center, Laval University, Quebec City, QC G1V 4G2, CanadaAxe Molecular Endocrinology and Nephrology, CHU Research Center, Laval University, Quebec City, QC G1V 4G2, CanadaSARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. The Omicron XBB subvariant, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (human Angiotensin-Converting Enzyme 2). Here we utilized multiligand virtual screening to identify small molecule inhibitors for their efficacy against SARS-CoV-2 virus using QPLD, pseudovirus ACE2 Inhibition -Time Resolved Forster/Fluorescence energy transfer (TR-FRET) Assay Screening, and Molecular Dynamics simulations (MDS). Three hundred and fifty thousand compounds were screened against the macrodomain of the nonstructural protein 3 of SARS-CoV-2. Using TR-FRET Assay, we filtered out two of 10 compounds that had no reported activity in in vitro screen against Spike S1: ACE2 binding assay. The percentage inhibition at 30 µM was found to be 79% for “Compound F1877-0839” and 69% for “Compound F0470-0003”. This first of its kind study identified “FILLY” pocket in macrodomains. Our 200 ns MDS revealed stable binding poses of both leads. They can be used for further development of preclinical candidates.https://www.mdpi.com/2306-5354/10/8/961SARS-CoV-2pseudovirus ACE2 InhibitionCOVID-19entry inhibitorsvirtual screeningmolecular dynamic simulations |
| spellingShingle | Saleem Iqbal Sheng-Xiang Lin Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations Bioengineering SARS-CoV-2 pseudovirus ACE2 Inhibition COVID-19 entry inhibitors virtual screening molecular dynamic simulations |
| title | Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations |
| title_full | Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations |
| title_fullStr | Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations |
| title_full_unstemmed | Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations |
| title_short | Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations |
| title_sort | deep drug discovery of mac domain of sars cov 2 wt spike inhibitors using experimental ace2 inhibition tr fret assay screening molecular dynamic simulations and free energy calculations |
| topic | SARS-CoV-2 pseudovirus ACE2 Inhibition COVID-19 entry inhibitors virtual screening molecular dynamic simulations |
| url | https://www.mdpi.com/2306-5354/10/8/961 |
| work_keys_str_mv | AT saleemiqbal deepdrugdiscoveryofmacdomainofsarscov2wtspikeinhibitorsusingexperimentalace2inhibitiontrfretassayscreeningmoleculardynamicsimulationsandfreeenergycalculations AT shengxianglin deepdrugdiscoveryofmacdomainofsarscov2wtspikeinhibitorsusingexperimentalace2inhibitiontrfretassayscreeningmoleculardynamicsimulationsandfreeenergycalculations |