Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease
The monkeypox virus (MPXV) is an enveloped, double-stranded DNA virus belonging to the genus Orthopox viruses. In recent years, the virus has spread to countries where it was previously unknown, turning it into a worldwide emergency for public health. This study employs a structural-based drug desig...
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MDPI AG
2023-07-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/7/2025 |
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| author | Mohd Imran Abida Nawaf M. Alotaibi Hamdy Khamees Thabet Jamal Alhameedi Alruwaili Lina Eltaib Ahmed Alshehri Ahad Amer Alsaiari Mehnaz Kamal Abdulmajeed Mohammed Abdullah Alshammari |
| author_facet | Mohd Imran Abida Nawaf M. Alotaibi Hamdy Khamees Thabet Jamal Alhameedi Alruwaili Lina Eltaib Ahmed Alshehri Ahad Amer Alsaiari Mehnaz Kamal Abdulmajeed Mohammed Abdullah Alshammari |
| author_sort | Mohd Imran |
| collection | DOAJ |
| description | The monkeypox virus (MPXV) is an enveloped, double-stranded DNA virus belonging to the genus Orthopox viruses. In recent years, the virus has spread to countries where it was previously unknown, turning it into a worldwide emergency for public health. This study employs a structural-based drug design approach to identify potential inhibitors for the core cysteine proteinase of MPXV. During the simulations, the study identified two potential inhibitors, compound CHEMBL32926 and compound CHEMBL4861364, demonstrating strong binding affinities and drug-like properties. Their docking scores with the target protein were −10.7 and −10.9 kcal/mol, respectively. This study used ensemble-based protein–ligand docking to account for the binding site conformation variability. By examining how the identified inhibitors interact with the protein, this research sheds light on the workings of the inhibitors’ mechanisms of action. Molecular dynamic simulations of protein–ligand complexes showed fluctuations from the initial docked pose, but they confirmed their binding throughout the simulation. The MMGBSA binding free energy calculations for CHEMBL32926 showed a binding free energy range of (−9.25 to −9.65) kcal/mol, while CHEMBL4861364 exhibited a range of (−41.66 to −31.47) kcal/mol. Later, analogues were searched for these compounds with 70% similarity criteria, and their IC<sub>50</sub> was predicted using pre-trained machine learning models. This resulted in identifying two similar compounds for each hit with comparable binding affinity for cysteine proteinase. This study’s structure-based drug design approach provides a promising strategy for identifying new drugs for treating MPXV infections. |
| first_indexed | 2024-03-11T01:17:04Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T01:17:04Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-d5e7ca9e020148b29b3a73a52cc0250e2023-11-18T18:28:23ZengMDPI AGBiomedicines2227-90592023-07-01117202510.3390/biomedicines11072025Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine ProteaseMohd Imran0Abida1Nawaf M. Alotaibi2Hamdy Khamees Thabet3Jamal Alhameedi Alruwaili4Lina Eltaib5Ahmed Alshehri6Ahad Amer Alsaiari7Mehnaz Kamal8Abdulmajeed Mohammed Abdullah Alshammari9Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi ArabiaDepartment of Clinical Pharmacy, College of Pharmacy, Northern Border University, Rafha 91911, Saudi ArabiaChemistry Department, College of Arts and Sciences, Northern Border University, Rafha 91911, Saudi ArabiaMedical Lab Technology Department, College of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, Northern Border University, Rafha 91911, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, Northern Border University, Rafha 91911, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi ArabiaCollege of Pharmacy, Northern Border University, Rafha 91911, Saudi ArabiaThe monkeypox virus (MPXV) is an enveloped, double-stranded DNA virus belonging to the genus Orthopox viruses. In recent years, the virus has spread to countries where it was previously unknown, turning it into a worldwide emergency for public health. This study employs a structural-based drug design approach to identify potential inhibitors for the core cysteine proteinase of MPXV. During the simulations, the study identified two potential inhibitors, compound CHEMBL32926 and compound CHEMBL4861364, demonstrating strong binding affinities and drug-like properties. Their docking scores with the target protein were −10.7 and −10.9 kcal/mol, respectively. This study used ensemble-based protein–ligand docking to account for the binding site conformation variability. By examining how the identified inhibitors interact with the protein, this research sheds light on the workings of the inhibitors’ mechanisms of action. Molecular dynamic simulations of protein–ligand complexes showed fluctuations from the initial docked pose, but they confirmed their binding throughout the simulation. The MMGBSA binding free energy calculations for CHEMBL32926 showed a binding free energy range of (−9.25 to −9.65) kcal/mol, while CHEMBL4861364 exhibited a range of (−41.66 to −31.47) kcal/mol. Later, analogues were searched for these compounds with 70% similarity criteria, and their IC<sub>50</sub> was predicted using pre-trained machine learning models. This resulted in identifying two similar compounds for each hit with comparable binding affinity for cysteine proteinase. This study’s structure-based drug design approach provides a promising strategy for identifying new drugs for treating MPXV infections.https://www.mdpi.com/2227-9059/11/7/2025monkeypox viruscysteine proteinasein silico methodsmolecular dockingmolecular dynamic simulations |
| spellingShingle | Mohd Imran Abida Nawaf M. Alotaibi Hamdy Khamees Thabet Jamal Alhameedi Alruwaili Lina Eltaib Ahmed Alshehri Ahad Amer Alsaiari Mehnaz Kamal Abdulmajeed Mohammed Abdullah Alshammari Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease Biomedicines monkeypox virus cysteine proteinase in silico methods molecular docking molecular dynamic simulations |
| title | Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease |
| title_full | Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease |
| title_fullStr | Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease |
| title_full_unstemmed | Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease |
| title_short | Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease |
| title_sort | repurposing anti dengue compounds against monkeypox virus targeting core cysteine protease |
| topic | monkeypox virus cysteine proteinase in silico methods molecular docking molecular dynamic simulations |
| url | https://www.mdpi.com/2227-9059/11/7/2025 |
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