Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations
The rise of β-Lactamase mediated antibiotic resistance is a major concern for public health; hence, there is an urgent need to find new treatment approaches. Structure-guided drug repurposing offers a promising approach to swiftly deliver essential therapeutics in the fight against escalating antibi...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-11-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1459822/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850199599559475200 |
|---|---|
| author | Moyad Shahwan Moyad Shahwan Mohd Shahnawaz Khan Azna Zuberi Nojood Altwaijry Anas Shamsi |
| author_facet | Moyad Shahwan Moyad Shahwan Mohd Shahnawaz Khan Azna Zuberi Nojood Altwaijry Anas Shamsi |
| author_sort | Moyad Shahwan |
| collection | DOAJ |
| description | The rise of β-Lactamase mediated antibiotic resistance is a major concern for public health; hence, there is an urgent need to find new treatment approaches. Structure-guided drug repurposing offers a promising approach to swiftly deliver essential therapeutics in the fight against escalating antibiotic resistance. Here, a structure-guided virtual screening approach was used involving drug profiling, molecular docking, and molecular dynamics (MD) simulation to identify existing drugs against β-Lactamase-associated drug resistance. We exploited a large panel of FDA-approved drugs to an extensive in silico analysis to ascertain their ability to inhibit β-Lactamase. First, molecular docking investigations were performed to assess the binding affinities and interactions of screened molecules with the active site of β-Lactamase enzymes. Out of all the screened candidates, Aristospan was identified to possess promising characteristics, which include appropriate drug profiles, high binding specificity, and efficiency towards the binding pocket of β-Lactamase. Further analysis showed that Aristospan possesses several desirable biological characteristics and tends to bind to the β-Lactamase binding site. To explore the interactions further, the best docking pose of Aristospan was selected for MD simulations to assess the thermodynamic stability of the drug-enzyme complex and its conformational changes over 500 ns. The MD simulations in independent replica runs demonstrated that the β-Lactamase-Aristospan complex was stable in the 500 ns trajectory. These enlightening results suggest that Aristospan may harbor the potential for further evolution into a possible β-Lactamase inhibitor, with potential applications in overcoming antibiotic resistance in both Gram-positive and Gram-negative bacteria. |
| format | Article |
| id | doaj-art-db80bf1bebb94f74b1c95674b1ad934d |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-db80bf1bebb94f74b1c95674b1ad934d2025-08-20T02:12:34ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-11-011510.3389/fphar.2024.14598221459822Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulationsMoyad Shahwan0Moyad Shahwan1Mohd Shahnawaz Khan2Azna Zuberi3Nojood Altwaijry4Anas Shamsi5Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab EmiratesCollege of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab EmiratesDepartment of Biochemistry, College of Science, King Saud University, Riyadh, Saudi ArabiaDivision of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Biochemistry, College of Science, King Saud University, Riyadh, Saudi ArabiaCenter for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab EmiratesThe rise of β-Lactamase mediated antibiotic resistance is a major concern for public health; hence, there is an urgent need to find new treatment approaches. Structure-guided drug repurposing offers a promising approach to swiftly deliver essential therapeutics in the fight against escalating antibiotic resistance. Here, a structure-guided virtual screening approach was used involving drug profiling, molecular docking, and molecular dynamics (MD) simulation to identify existing drugs against β-Lactamase-associated drug resistance. We exploited a large panel of FDA-approved drugs to an extensive in silico analysis to ascertain their ability to inhibit β-Lactamase. First, molecular docking investigations were performed to assess the binding affinities and interactions of screened molecules with the active site of β-Lactamase enzymes. Out of all the screened candidates, Aristospan was identified to possess promising characteristics, which include appropriate drug profiles, high binding specificity, and efficiency towards the binding pocket of β-Lactamase. Further analysis showed that Aristospan possesses several desirable biological characteristics and tends to bind to the β-Lactamase binding site. To explore the interactions further, the best docking pose of Aristospan was selected for MD simulations to assess the thermodynamic stability of the drug-enzyme complex and its conformational changes over 500 ns. The MD simulations in independent replica runs demonstrated that the β-Lactamase-Aristospan complex was stable in the 500 ns trajectory. These enlightening results suggest that Aristospan may harbor the potential for further evolution into a possible β-Lactamase inhibitor, with potential applications in overcoming antibiotic resistance in both Gram-positive and Gram-negative bacteria.https://www.frontiersin.org/articles/10.3389/fphar.2024.1459822/fullβ-lactamaseantibiotic resistancedrug repurposingvirtual screeningmolecular dynamics simulationSM23 |
| spellingShingle | Moyad Shahwan Moyad Shahwan Mohd Shahnawaz Khan Azna Zuberi Nojood Altwaijry Anas Shamsi Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations Frontiers in Pharmacology β-lactamase antibiotic resistance drug repurposing virtual screening molecular dynamics simulation SM23 |
| title | Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations |
| title_full | Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations |
| title_fullStr | Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations |
| title_full_unstemmed | Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations |
| title_short | Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations |
| title_sort | structure guided drug repurposing identifies aristospan as a potential inhibitor of β lactamase insights from virtual screening and molecular dynamics simulations |
| topic | β-lactamase antibiotic resistance drug repurposing virtual screening molecular dynamics simulation SM23 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1459822/full |
| work_keys_str_mv | AT moyadshahwan structureguideddrugrepurposingidentifiesaristospanasapotentialinhibitorofblactamaseinsightsfromvirtualscreeningandmoleculardynamicssimulations AT moyadshahwan structureguideddrugrepurposingidentifiesaristospanasapotentialinhibitorofblactamaseinsightsfromvirtualscreeningandmoleculardynamicssimulations AT mohdshahnawazkhan structureguideddrugrepurposingidentifiesaristospanasapotentialinhibitorofblactamaseinsightsfromvirtualscreeningandmoleculardynamicssimulations AT aznazuberi structureguideddrugrepurposingidentifiesaristospanasapotentialinhibitorofblactamaseinsightsfromvirtualscreeningandmoleculardynamicssimulations AT nojoodaltwaijry structureguideddrugrepurposingidentifiesaristospanasapotentialinhibitorofblactamaseinsightsfromvirtualscreeningandmoleculardynamicssimulations AT anasshamsi structureguideddrugrepurposingidentifiesaristospanasapotentialinhibitorofblactamaseinsightsfromvirtualscreeningandmoleculardynamicssimulations |