In Vitro Screening and MD Simulations of Thiourea Derivatives against SARS-CoV-2 in Association with Multidrug Resistance ABCB1 Transporter
© 2022 The Authors. Published by American Chemical Society..
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is considered a global public health concern since it causes high morbidity and mortality. Recently, it has been reported that repurposed anti-COVID-19 drugs might interact with multidrug resistance ABC transporter, particularly ABCB1. In the current study, a series of thiourea derivatives were screened as potential inhibitors against SARS-CoV-2 by targeting the attachment of receptor binding domain (RBD) of spike protein with ACE2 and their interaction with human ABCB1 has also been explored. The results indicated strong impairment of RBD-ACE2 attachment by BB IV-46 with a percentage inhibition of 95.73 ± 1.79% relative to the positive control, while BB V-19 was proven inactive with a percentage inhibition of 50.90 ± 0.84%. The same compound (BB IV-46) interacted with ABCB1 and potentially inhibited cell proliferation of P-gp overexpressing cell line with an IC50 value of 4.651 ± 0.06 μM. BB V-19, which was inactive against SARS-CoV-2, was inactive against ABCB1 with a higher IC50 value of 35.72 ± 0.09 μM. Furthermore, molecular dynamics simulations followed by binding free-energy analysis explored the binding interaction of BB IV-46 and BB V-19 to RBD region of spike protein of SARS-CoV-2. The results confirmed that compound BB IV-46 interacted strongly with RBD with a significant binding energy (-127.0 kJ/mol), while BB V-19 interacted weakly (-29.30 kJ/mol). The key interacting residues of the RBD involved in binding included Leu441, Lys444, and Tyr449. This study highlights the importance of BB IV-46 against SARS-CoV-2; however, further pharmacokinetic and pharmacodynamics studies are needed to be done.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
ACS omega - 7(2022), 51 vom: 27. Dez., Seite 47671-47679 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Assad, Mohammad [VerfasserIn] |
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| Anmerkungen: |
Date Revised 27.12.2022 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/acsomega.2c04671 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is considered a global public health concern since it causes high morbidity and mortality. Recently, it has been reported that repurposed anti-COVID-19 drugs might interact with multidrug resistance ABC transporter, particularly ABCB1. In the current study, a series of thiourea derivatives were screened as potential inhibitors against SARS-CoV-2 by targeting the attachment of receptor binding domain (RBD) of spike protein with ACE2 and their interaction with human ABCB1 has also been explored. The results indicated strong impairment of RBD-ACE2 attachment by BB IV-46 with a percentage inhibition of 95.73 ± 1.79% relative to the positive control, while BB V-19 was proven inactive with a percentage inhibition of 50.90 ± 0.84%. The same compound (BB IV-46) interacted with ABCB1 and potentially inhibited cell proliferation of P-gp overexpressing cell line with an IC50 value of 4.651 ± 0.06 μM. BB V-19, which was inactive against SARS-CoV-2, was inactive against ABCB1 with a higher IC50 value of 35.72 ± 0.09 μM. Furthermore, molecular dynamics simulations followed by binding free-energy analysis explored the binding interaction of BB IV-46 and BB V-19 to RBD region of spike protein of SARS-CoV-2. The results confirmed that compound BB IV-46 interacted strongly with RBD with a significant binding energy (-127.0 kJ/mol), while BB V-19 interacted weakly (-29.30 kJ/mol). The key interacting residues of the RBD involved in binding included Leu441, Lys444, and Tyr449. This study highlights the importance of BB IV-46 against SARS-CoV-2; however, further pharmacokinetic and pharmacodynamics studies are needed to be done | ||
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| 700 | 1 | |a Khurshid, Beenish |e verfasserin |4 aut | |
| 700 | 1 | |a Hashmi, Muhammad Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Khalid Mohammed |e verfasserin |4 aut | |
| 700 | 1 | |a Khurshid, Akif |e verfasserin |4 aut | |
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