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Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach

Parvez et al., International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.098
Nov 2020  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.
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In Silico study showing that ivermectin, rifabutin, rifapentine, fidaxomicin, and 7-methyl-guanosine-5′-triphosphate-5′-guanosine could be potential inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Authors used molecular docking to screen 44 RNA polymerase inhibitor drug candidates, finding that these five compounds had the highest binding affinity to RdRp, even higher than remdesivir and favipiravir which were used as positive controls. The amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 in RdRp were identified as a potential common drug surface hotspot for interaction with the inhibitors.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), inhibits SARS-CoV-2 3CLpro Mody, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
Parvez et al., 30 Nov 2020, peer-reviewed, 8 authors. Contact:,
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach
Md. Sorwer Alam Parvez, Md. Adnan Karim, Mahmudul Hasan, Jomana Jaman, Ziaul Karim, Tohura Tahsin, Md. Nazmul Hasan, Mohammad Jakir Hosen
International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.098
The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNAdependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5′-triphosphate-5′-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.
Fig. 10 . PCA results trejectories for the protein-inhibitor complexes. Here, RdRp in complex with (A) Rifabutin, (B) ZINC09128258, and (C) ZINC098833. In this graph, the colour blue to red frames over time. Declaration of competing interest The authors declare that they have no competing interests.
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