Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme
With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The pur...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/5/1446 |
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| author | Sajjad Ahmad Yasir Waheed Saba Ismail Saadia Bhatti Sumra Wajid Abbasi Khalid Muhammad |
| author_facet | Sajjad Ahmad Yasir Waheed Saba Ismail Saadia Bhatti Sumra Wajid Abbasi Khalid Muhammad |
| author_sort | Sajjad Ahmad |
| collection | DOAJ |
| description | With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of −9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of −10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19. |
| first_indexed | 2024-03-09T05:05:43Z |
| format | Article |
| id | doaj.art-1ad3e37dafbb4eb1a785e8bc8d010edf |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T05:05:43Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1ad3e37dafbb4eb1a785e8bc8d010edf2023-12-03T12:54:49ZengMDPI AGMolecules1420-30492021-03-01265144610.3390/molecules26051446Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase EnzymeSajjad Ahmad0Yasir Waheed1Saba Ismail2Saadia Bhatti3Sumra Wajid Abbasi4Khalid Muhammad5Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad 44000, PakistanFoundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad 44000, PakistanFoundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad 44000, PakistanDepartment of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 44000, PakistanNUMS Department of Biological Sciences, National University of Medical Sciences, Abid Majeed Rd, The Mall, Rawalpindi 46000, PakistanDepartment of Biology, College of Science, United Arab Emirates University, Al Ain 15551, United Arab EmiratesWith the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of −9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of −10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.https://www.mdpi.com/1420-3049/26/5/1446SARS-CoV-2 helicaseCOVID-19molecular dynamic simulationphytochemicals |
| spellingShingle | Sajjad Ahmad Yasir Waheed Saba Ismail Saadia Bhatti Sumra Wajid Abbasi Khalid Muhammad Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme Molecules SARS-CoV-2 helicase COVID-19 molecular dynamic simulation phytochemicals |
| title | Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme |
| title_full | Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme |
| title_fullStr | Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme |
| title_full_unstemmed | Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme |
| title_short | Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme |
| title_sort | structure based virtual screening identifies multiple stable binding sites at the reca domains of sars cov 2 helicase enzyme |
| topic | SARS-CoV-2 helicase COVID-19 molecular dynamic simulation phytochemicals |
| url | https://www.mdpi.com/1420-3049/26/5/1446 |
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