A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein
There are an estimated 3 million Chikungunya virus (CHIKV) infections per year, but no vaccines or specific pharmaceutical treatments are available. RNA-dependent RNA polymerase (RdRp) of CHIKV, encoded by nonstructural protein 4 (nsP4), was targeted to identify potential antiviral compounds in this...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Chemical Physics Impact |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S266702242300289X |
| _version_ | 1797365557286141952 |
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| author | Md. Hridoy Ahmed Gagandeep Singh Melvin Castrosanto Alomgir Hossain Md. Morshedul Islam Rifat Sadia Hosna Rima Vandana Gupta Rajesh K. Kesharwani Mariusz Jaremko Abdul-Hamid Emwas Prawez Alam Faizul Azam |
| author_facet | Md. Hridoy Ahmed Gagandeep Singh Melvin Castrosanto Alomgir Hossain Md. Morshedul Islam Rifat Sadia Hosna Rima Vandana Gupta Rajesh K. Kesharwani Mariusz Jaremko Abdul-Hamid Emwas Prawez Alam Faizul Azam |
| author_sort | Md. Hridoy Ahmed |
| collection | DOAJ |
| description | There are an estimated 3 million Chikungunya virus (CHIKV) infections per year, but no vaccines or specific pharmaceutical treatments are available. RNA-dependent RNA polymerase (RdRp) of CHIKV, encoded by nonstructural protein 4 (nsP4), was targeted to identify potential antiviral compounds in this study. A 3D model of the nsP4 was generated by homology modeling technique and Pockdrug-Server was used to predict ligand binding sites. The pharmacophore hypothesis was developed followed by virtual screening. 300 most potential ligands were selected from a library of 3000 compounds, after filtering for the molecules satisfying Lipinski's Rule of Five. Using molecular docking followed by ADMET analysis, 27 leads were then selected. We used MD simulations of the three best compounds that bind to the catalytic, palm, and thumb domains to find out how the ligand-protein interactions change over time. RMSD, RMSF, radius of gyration, free energy landscapes, and principal component analyses revealed that complexes nsP4-ZINC-12820763 and nsP4-ZINC-33280972 were more stable. Simulated trajectories were further used to compute MMGBSA binding energies of PubChem-135638918 (-22.33 kcal/mol), ZINC-12820763 (-50.19 kcal/mol) and ZINC-33280972 (-32.69 kcal/mol) bound to catalytic, palm and thumb domains, respectively. HOMO and LUMO of potential molecules were also investigated using density functional theory computations. With the support of computational simulations, three compounds were shown to have the potential to inhibit RdRp of CHIKV and need further evaluation using in-vitro and in-vivo analysis. |
| first_indexed | 2024-03-08T16:50:41Z |
| format | Article |
| id | doaj.art-0dc7b8b8a1a046daaf3308b01a5a0abd |
| institution | Directory Open Access Journal |
| issn | 2667-0224 |
| language | English |
| last_indexed | 2024-03-08T16:50:41Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Chemical Physics Impact |
| spelling | doaj.art-0dc7b8b8a1a046daaf3308b01a5a0abd2024-01-05T04:25:21ZengElsevierChemical Physics Impact2667-02242024-06-018100450A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp proteinMd. Hridoy Ahmed0Gagandeep Singh1Melvin Castrosanto2Alomgir Hossain3Md. Morshedul Islam Rifat4Sadia Hosna Rima5Vandana Gupta6Rajesh K. Kesharwani7Mariusz Jaremko8Abdul-Hamid Emwas9Prawez Alam10Faizul Azam11Department of Genetic Engineering and Biotechnology, University of Chittagong, Chittagong, BangladeshSection of Microbiology, Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, India; Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, IndiaInstitute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, PhilippinesDepartment of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, BangladeshDepartment of Genetic Engineering and Biotechnology, University of Chittagong, Chittagong, BangladeshDepartment of Genetic Engineering and Biotechnology, University of Chittagong, Chittagong, BangladeshDepartment of Microbiology, Ram Lal Anand College, University of Delhi, IndiaDepartment of Computer Application, Nehru Gram Bharati (Deemed to be University), Prayagraj, IndiaSmart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Jeddah, Saudi ArabiaCore Labs, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi ArabiaDepartment of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi ArabiaDepartment of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia; Corresponding author.There are an estimated 3 million Chikungunya virus (CHIKV) infections per year, but no vaccines or specific pharmaceutical treatments are available. RNA-dependent RNA polymerase (RdRp) of CHIKV, encoded by nonstructural protein 4 (nsP4), was targeted to identify potential antiviral compounds in this study. A 3D model of the nsP4 was generated by homology modeling technique and Pockdrug-Server was used to predict ligand binding sites. The pharmacophore hypothesis was developed followed by virtual screening. 300 most potential ligands were selected from a library of 3000 compounds, after filtering for the molecules satisfying Lipinski's Rule of Five. Using molecular docking followed by ADMET analysis, 27 leads were then selected. We used MD simulations of the three best compounds that bind to the catalytic, palm, and thumb domains to find out how the ligand-protein interactions change over time. RMSD, RMSF, radius of gyration, free energy landscapes, and principal component analyses revealed that complexes nsP4-ZINC-12820763 and nsP4-ZINC-33280972 were more stable. Simulated trajectories were further used to compute MMGBSA binding energies of PubChem-135638918 (-22.33 kcal/mol), ZINC-12820763 (-50.19 kcal/mol) and ZINC-33280972 (-32.69 kcal/mol) bound to catalytic, palm and thumb domains, respectively. HOMO and LUMO of potential molecules were also investigated using density functional theory computations. With the support of computational simulations, three compounds were shown to have the potential to inhibit RdRp of CHIKV and need further evaluation using in-vitro and in-vivo analysis.http://www.sciencedirect.com/science/article/pii/S266702242300289XChikungunyaHomology modelingE-pharmacophoreMolecular dockingMolecular dynamics |
| spellingShingle | Md. Hridoy Ahmed Gagandeep Singh Melvin Castrosanto Alomgir Hossain Md. Morshedul Islam Rifat Sadia Hosna Rima Vandana Gupta Rajesh K. Kesharwani Mariusz Jaremko Abdul-Hamid Emwas Prawez Alam Faizul Azam A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein Chemical Physics Impact Chikungunya Homology modeling E-pharmacophore Molecular docking Molecular dynamics |
| title | A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein |
| title_full | A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein |
| title_fullStr | A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein |
| title_full_unstemmed | A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein |
| title_short | A structure-based drug design approach for the identification of antiviral compounds targeting the chikungunya virus RdRp protein |
| title_sort | structure based drug design approach for the identification of antiviral compounds targeting the chikungunya virus rdrp protein |
| topic | Chikungunya Homology modeling E-pharmacophore Molecular docking Molecular dynamics |
| url | http://www.sciencedirect.com/science/article/pii/S266702242300289X |
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