Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2
SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/6/1406 |
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| author | Kirti Sharma Manjinder Singh Pratibha Sharma Sumesh C. Sharma Somdutt Mujwar Mohit Kapoor Krishna Kumar Mishra Tanveer A. Wani |
| author_facet | Kirti Sharma Manjinder Singh Pratibha Sharma Sumesh C. Sharma Somdutt Mujwar Mohit Kapoor Krishna Kumar Mishra Tanveer A. Wani |
| author_sort | Kirti Sharma |
| collection | DOAJ |
| description | SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The M<sup>pro</sup> of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 M<sup>Pro</sup> to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds <b>KS82</b> and <b>KS94</b> was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules <b>KS82</b> and <b>KS94</b> were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties. |
| first_indexed | 2024-04-24T17:58:03Z |
| format | Article |
| id | doaj.art-2a42876fa0324a53a90033f23b733da0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-24T17:58:03Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-2a42876fa0324a53a90033f23b733da02024-03-27T13:57:18ZengMDPI AGMolecules1420-30492024-03-01296140610.3390/molecules29061406Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2Kirti Sharma0Manjinder Singh1Pratibha Sharma2Sumesh C. Sharma3Somdutt Mujwar4Mohit Kapoor5Krishna Kumar Mishra6Tanveer A. Wani7Chitkara Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, IndiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaSARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The M<sup>pro</sup> of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 M<sup>Pro</sup> to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds <b>KS82</b> and <b>KS94</b> was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules <b>KS82</b> and <b>KS94</b> were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties.https://www.mdpi.com/1420-3049/29/6/1406SARS-CoV-2M<sup>Pro</sup>nsP3scaffold morphingmolecular docking |
| spellingShingle | Kirti Sharma Manjinder Singh Pratibha Sharma Sumesh C. Sharma Somdutt Mujwar Mohit Kapoor Krishna Kumar Mishra Tanveer A. Wani Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2 Molecules SARS-CoV-2 M<sup>Pro</sup> nsP3 scaffold morphing molecular docking |
| title | Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2 |
| title_full | Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2 |
| title_fullStr | Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2 |
| title_full_unstemmed | Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2 |
| title_short | Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2 |
| title_sort | design synthesis and biological evaluation of novel coumarin analogs targeted against sars cov 2 |
| topic | SARS-CoV-2 M<sup>Pro</sup> nsP3 scaffold morphing molecular docking |
| url | https://www.mdpi.com/1420-3049/29/6/1406 |
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