Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors
Staphylococcus epidermidis is the most common cause of medical device-associated infections and is an opportunistic biofilm former. Among hospitalized patients, S. epidermidis infections are the most prevalent, and resistant to most antibiotics. In order to overcome this resistance, it is imperative...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1087676/full |
| _version_ | 1811160774460047360 |
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| author | Divya Vemula Dhanashri Ramesh Maddi Vasundhra Bhandari |
| author_facet | Divya Vemula Dhanashri Ramesh Maddi Vasundhra Bhandari |
| author_sort | Divya Vemula |
| collection | DOAJ |
| description | Staphylococcus epidermidis is the most common cause of medical device-associated infections and is an opportunistic biofilm former. Among hospitalized patients, S. epidermidis infections are the most prevalent, and resistant to most antibiotics. In order to overcome this resistance, it is imperative to treat the infection at a cellular level. The present study aims to identify inhibitors of the prokaryotic cell division protein FtsZ a widely conserved component of bacterial cytokinesis. Two substrate binding sites are present on the FtsZ protein; the nucleotide-binding domain and the inter-domain binding sites. Molecular modeling was used to identify potential inhibitors against the binding sites of the FtsZ protein. One hundred thirty-eight chemical entities were virtually screened for the binding sites and revealed ten molecules, each with good binding affinities (docking score range −9.549 to −4.290 kcal/mol) compared to the reference control drug, i.e., Dacomitinib (−4.450 kcal/mol) and PC190723 (−4.694 kcal/mol) at nucleotide and inter-domain binding sites respectively. These top 10 hits were further analyzed for their ADMET properties and molecular dynamics simulations. The Chloro-derivative of GTP, naphthalene-1,3-diyl bis(3,4,5-trihydroxybenzoate), Guanosine triphosphate (GTP), morpholine and methylpiperazine derivative of GTP were identified as the lead molecules for nucleotide binding site whereas for inter-domain binding site, 1-(((amino(iminio)methyl)amino)methyl)-3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinolin-2-ium, and Chlorogenic acidwere identified as lead molecules. Molecular dynamics simulation and post MM/GBSA analysis of the complexes revealed good protein-ligand stability predicting them as potential inhibitors of FtsZ (Figure 1). Thus, identified FtsZ inhibitors are a promising lead compounds for S. epidermidis related infections. |
| first_indexed | 2024-04-10T06:03:12Z |
| format | Article |
| id | doaj.art-d215984e8ad8472fb42b04fc88e20b75 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-10T06:03:12Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-d215984e8ad8472fb42b04fc88e20b752023-03-03T05:52:29ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-03-011010.3389/fmolb.2023.10876761087676Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitorsDivya VemulaDhanashri Ramesh MaddiVasundhra BhandariStaphylococcus epidermidis is the most common cause of medical device-associated infections and is an opportunistic biofilm former. Among hospitalized patients, S. epidermidis infections are the most prevalent, and resistant to most antibiotics. In order to overcome this resistance, it is imperative to treat the infection at a cellular level. The present study aims to identify inhibitors of the prokaryotic cell division protein FtsZ a widely conserved component of bacterial cytokinesis. Two substrate binding sites are present on the FtsZ protein; the nucleotide-binding domain and the inter-domain binding sites. Molecular modeling was used to identify potential inhibitors against the binding sites of the FtsZ protein. One hundred thirty-eight chemical entities were virtually screened for the binding sites and revealed ten molecules, each with good binding affinities (docking score range −9.549 to −4.290 kcal/mol) compared to the reference control drug, i.e., Dacomitinib (−4.450 kcal/mol) and PC190723 (−4.694 kcal/mol) at nucleotide and inter-domain binding sites respectively. These top 10 hits were further analyzed for their ADMET properties and molecular dynamics simulations. The Chloro-derivative of GTP, naphthalene-1,3-diyl bis(3,4,5-trihydroxybenzoate), Guanosine triphosphate (GTP), morpholine and methylpiperazine derivative of GTP were identified as the lead molecules for nucleotide binding site whereas for inter-domain binding site, 1-(((amino(iminio)methyl)amino)methyl)-3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinolin-2-ium, and Chlorogenic acidwere identified as lead molecules. Molecular dynamics simulation and post MM/GBSA analysis of the complexes revealed good protein-ligand stability predicting them as potential inhibitors of FtsZ (Figure 1). Thus, identified FtsZ inhibitors are a promising lead compounds for S. epidermidis related infections.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1087676/fullFtsZStaphylococcus epidermidisinsilico analysismolecular modeling and simulationvirtual screeening |
| spellingShingle | Divya Vemula Dhanashri Ramesh Maddi Vasundhra Bhandari Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors Frontiers in Molecular Biosciences FtsZ Staphylococcus epidermidis insilico analysis molecular modeling and simulation virtual screeening |
| title | Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors |
| title_full | Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors |
| title_fullStr | Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors |
| title_full_unstemmed | Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors |
| title_short | Homology modeling, virtual screening, molecular docking, and dynamics studies for discovering Staphylococcus epidermidis FtsZ inhibitors |
| title_sort | homology modeling virtual screening molecular docking and dynamics studies for discovering staphylococcus epidermidis ftsz inhibitors |
| topic | FtsZ Staphylococcus epidermidis insilico analysis molecular modeling and simulation virtual screeening |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1087676/full |
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