Unlocking therapeutic potential : computational insights into TREM2 protein targeting with FDA-approved drugs for neurodegeneration
Neurodegenerative diseases such as Alzheimer's disease (AD) pose a significant global health challenge that requires the exploration of innovative therapeutic strategies. Triggering receptor expressed on myeloid cells-2 (TREM2) is one of the critical proteins involved in immune regulation and neuroinflammation. It has emerged as a promising therapeutic target to develop treatments for neurodegenerative disorders like AD. Here, we employed a comprehensive virtual screening approach to identify potential small molecule inhibitors among FDA-approved drugs for TREM2. The docking study reveals significant binding affinity, ranging from -7.8 kcal/mol to -8.5 kcal/mol, for the elucidated hits against TREM2, accompanied by several crucial interactions. Among the repurposed drugs identified in the initial screening, Carpipramine, Clocapramine, and Pimozide stood out due to their notable binding potential and favorable drug profiling. Further, we conducted molecular dynamics (MD) simulations on the selected molecules that probed their structural dynamics and stability within the TREM2 binding pocket. The structural parameters and hydrogen bond dynamics remained remarkably stable throughout the simulated trajectories. Furthermore, we performed principal component analysis (PCA) and constructed free energy landscapes (FELs) to gain deeper insights into ligand binding and conformational flexibility of TREM2. The findings revealed that the elucidated molecules, Carpipramine, Clocapramine, and Pimozide, exhibited an exceptional fit within the binding pocket of TREM2 with remarkable stability and interaction patterns throughout the 500 ns simulation window. Interestingly, these molecules possessed a spectrum of anti-neurodegenerative properties and favorable drug profiles, which suggest their potential as promising drug candidates for repurposing in the treatment of AD.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: 19. Feb., Seite 1-11 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Alrouji, Mohammed [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Alzheimer’s disease |
|---|
| Anmerkungen: |
Date Revised 19.02.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1080/07391102.2024.2317987 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368631516 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368631516 | ||
| 003 | DE-627 | ||
| 005 | 20240220232351.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240220s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/07391102.2024.2317987 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1300.xml |
| 035 | |a (DE-627)NLM368631516 | ||
| 035 | |a (NLM)38373093 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Alrouji, Mohammed |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unlocking therapeutic potential |b computational insights into TREM2 protein targeting with FDA-approved drugs for neurodegeneration |
| 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 19.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Neurodegenerative diseases such as Alzheimer's disease (AD) pose a significant global health challenge that requires the exploration of innovative therapeutic strategies. Triggering receptor expressed on myeloid cells-2 (TREM2) is one of the critical proteins involved in immune regulation and neuroinflammation. It has emerged as a promising therapeutic target to develop treatments for neurodegenerative disorders like AD. Here, we employed a comprehensive virtual screening approach to identify potential small molecule inhibitors among FDA-approved drugs for TREM2. The docking study reveals significant binding affinity, ranging from -7.8 kcal/mol to -8.5 kcal/mol, for the elucidated hits against TREM2, accompanied by several crucial interactions. Among the repurposed drugs identified in the initial screening, Carpipramine, Clocapramine, and Pimozide stood out due to their notable binding potential and favorable drug profiling. Further, we conducted molecular dynamics (MD) simulations on the selected molecules that probed their structural dynamics and stability within the TREM2 binding pocket. The structural parameters and hydrogen bond dynamics remained remarkably stable throughout the simulated trajectories. Furthermore, we performed principal component analysis (PCA) and constructed free energy landscapes (FELs) to gain deeper insights into ligand binding and conformational flexibility of TREM2. The findings revealed that the elucidated molecules, Carpipramine, Clocapramine, and Pimozide, exhibited an exceptional fit within the binding pocket of TREM2 with remarkable stability and interaction patterns throughout the 500 ns simulation window. Interestingly, these molecules possessed a spectrum of anti-neurodegenerative properties and favorable drug profiles, which suggest their potential as promising drug candidates for repurposing in the treatment of AD.Communicated by Ramaswamy H. Sarma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alzheimer’s disease | |
| 650 | 4 | |a Triggering receptor expressed on myeloid cells-2 | |
| 650 | 4 | |a drug repurposing | |
| 650 | 4 | |a neurodegenerative diseases | |
| 650 | 4 | |a pharmacokinetic assessment | |
| 650 | 4 | |a virtual screening | |
| 700 | 1 | |a Yasmin, Sabina |e verfasserin |4 aut | |
| 700 | 1 | |a Alhumaydhi, Fahad A |e verfasserin |4 aut | |
| 700 | 1 | |a Sharaf, Sharaf E |e verfasserin |4 aut | |
| 700 | 1 | |a Shahwan, Moyad |e verfasserin |4 aut | |
| 700 | 1 | |a Shamsi, Anas |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of biomolecular structure & dynamics |d 1985 |g (2024) vom: 19. Feb., Seite 1-11 |w (DE-627)NLM012639974 |x 1538-0254 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:19 |g month:02 |g pages:1-11 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1080/07391102.2024.2317987 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 19 |c 02 |h 1-11 | ||