Repurposing of SARS-CoV-2 compounds against Marburg Virus using MD simulation, mm/GBSA, PCA analysis, and free energy landscape
The significant mortality rate associated with Marburg virus infection made it the greatest hazard among infectious diseases. Drug repurposing using in silico methods has been crucial in identifying potential compounds that could prevent viral replication by targeting the virus's primary proteins. This study aimed at repurposing the drugs of SARS-CoV-2 for identifying potential candidates against the matrix protein VP40 of the Marburg virus. Virtual screening was performed where the control compound, Nilotinib, showed a binding score of -9.99 kcal/mol. Based on binding scores, hit compounds 9549298, 11960895, 44545852, 51039094, and 89670174 were selected that had a lower binding score than the control. Subsequent molecular dynamics (MD) simulation revealed that compound 9549298 consistently formed a hydrogen bond with the residue Gln290. This was observed both in molecular docking and MD simulation poses, indicating a strong and significant interaction with the protein. 11960895 had the most stable and consistent RMSD pattern exhibited in 100 ns simulation, while 9549298 had the most identical RMSD plot compared to the control molecule. MM/PBSA analysis showed that the binding free energy (ΔG) of 9549298 and 11960895 was lower than the control, with -30.84 and -38.86 kcal/mol, respectively. It was observed by the PCA (principal component analysis) and FEL (free energy landscape) analysis that compounds 9549298 and 11960895 had lesser conformational variation. Overall, this study proposed 9549298 and 11960895 as potential binders of VP40 MARV that can cause its inhibition, however it inherently lacks experimental validation. Furthermore, the study proposes in-vitro experiments as the next step to validate these computational findings, offering a practical approach to further explore these compounds' potential as antiviral agents.Communicated by Ramaswamy H. Sarma.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
Journal of biomolecular structure & dynamics - (2024) vom: 07. März, Seite 1-20 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kumar, Sanjay [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Drug purposing |
|---|
| Anmerkungen: |
Date Revised 07.03.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1080/07391102.2024.2323701 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369404734 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369404734 | ||
| 003 | DE-627 | ||
| 005 | 20240307233155.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240307s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/07391102.2024.2323701 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1319.xml |
| 035 | |a (DE-627)NLM369404734 | ||
| 035 | |a (NLM)38450706 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Kumar, Sanjay |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Repurposing of SARS-CoV-2 compounds against Marburg Virus using MD simulation, mm/GBSA, PCA analysis, and free energy landscape |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 07.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a The significant mortality rate associated with Marburg virus infection made it the greatest hazard among infectious diseases. Drug repurposing using in silico methods has been crucial in identifying potential compounds that could prevent viral replication by targeting the virus's primary proteins. This study aimed at repurposing the drugs of SARS-CoV-2 for identifying potential candidates against the matrix protein VP40 of the Marburg virus. Virtual screening was performed where the control compound, Nilotinib, showed a binding score of -9.99 kcal/mol. Based on binding scores, hit compounds 9549298, 11960895, 44545852, 51039094, and 89670174 were selected that had a lower binding score than the control. Subsequent molecular dynamics (MD) simulation revealed that compound 9549298 consistently formed a hydrogen bond with the residue Gln290. This was observed both in molecular docking and MD simulation poses, indicating a strong and significant interaction with the protein. 11960895 had the most stable and consistent RMSD pattern exhibited in 100 ns simulation, while 9549298 had the most identical RMSD plot compared to the control molecule. MM/PBSA analysis showed that the binding free energy (ΔG) of 9549298 and 11960895 was lower than the control, with -30.84 and -38.86 kcal/mol, respectively. It was observed by the PCA (principal component analysis) and FEL (free energy landscape) analysis that compounds 9549298 and 11960895 had lesser conformational variation. Overall, this study proposed 9549298 and 11960895 as potential binders of VP40 MARV that can cause its inhibition, however it inherently lacks experimental validation. Furthermore, the study proposes in-vitro experiments as the next step to validate these computational findings, offering a practical approach to further explore these compounds' potential as antiviral agents.Communicated by Ramaswamy H. Sarma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a In silico study | |
| 650 | 4 | |a MD simulation and PCA | |
| 650 | 4 | |a Marburg virus | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a drug purposing | |
| 700 | 1 | |a Dubey, Rajni |e verfasserin |4 aut | |
| 700 | 1 | |a Mishra, Richa |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Saurabh |e verfasserin |4 aut | |
| 700 | 1 | |a Dwivedi, Vivek Dhar |e verfasserin |4 aut | |
| 700 | 1 | |a Ray, Subhasree |e verfasserin |4 aut | |
| 700 | 1 | |a Jha, Niraj Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Verma, Devvret |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Lung-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Dubey, Navneet Kumar |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of biomolecular structure & dynamics |d 1985 |g (2024) vom: 07. März, Seite 1-20 |w (DE-627)NLM012639974 |x 1538-0254 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:07 |g month:03 |g pages:1-20 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1080/07391102.2024.2323701 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 07 |c 03 |h 1-20 | ||