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Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies.
Abo Elmaaty, Ayman; Eldehna, Wagdy M; Khattab, Muhammad; Kutkat, Omnia; Alnajjar, Radwan; El-Taweel, Ahmed N; Al-Rashood, Sara T; Abourehab, Mohammed A S; Binjubair, Faizah A; Saleh, Mohamed A; Belal, Amany; Al-Karmalawy, Ahmed A.
  • Abo Elmaaty A; Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt.
  • Eldehna WM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • Khattab M; School of Biotechnology, Badr University in Cairo, Badr City 11829, Egypt.
  • Kutkat O; Department of Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Research Institute, National Research Centre, El-Buhouth St., Dokki, Cairo 12622, Egypt.
  • Alnajjar R; Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt.
  • El-Taweel AN; Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi 16063, Libya.
  • Al-Rashood ST; PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi 16063, Libya.
  • Abourehab MAS; Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
  • Binjubair FA; Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt.
  • Saleh MA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, United Arab Emirates.
  • Belal A; Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, United Arab Emirates.
  • Al-Karmalawy AA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, United Arab Emirates.
Int J Mol Sci ; 23(20)2022 Oct 13.
Article in English | MEDLINE | ID: covidwho-2071505
ABSTRACT
In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232012235

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232012235