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The potential of Paritaprevir and Emetine as inhibitors of SARS-CoV-2 RdRp.

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a well-characterized therapeutic target which is a key player driving the viral replication and transcription machinery. The recent elucidation of the experimental structure of SARS-CoV-2 RdRp enzyme complexed with triphosphate form of Remdesivir (RTP) has opened an avenue for structure-based identification of potent inhibitors. Given the high mortality rate of the coronavirus disease 2019 (COVID-19) and lack of effective therapeutics against it, an alternative for safe and speedy drug discovery needs to be sought after. One promising strategy could be to explore the possibility for repurposing the Food and Drug Administration (FDA) approved antiviral drugs and antiviral phytocompounds. In the present study, a set of FDA approved antiviral drugs and antiviral phytocompounds were screened for their ability to bind within the RdRp enzyme active pocket. The top 3 hits among the FDA approved drugs were Paritaprevir (D33), Rilpivirine (D19) and Simeprevir (D31) which scored binding energies between -8.08 kcal/mol and -10.46 kcal/mol. Emetine (P5), 7,4-di-O-galloyltricetifavan (P28) and Oleanolic acid (P17) were the top three phytocompounds hits and exhibited binding energies ranging from -7.81 kcal/mol to -8.17 kcal/mol. These drugs and phytocompounds were able to establish hydrogen bonds with the catalytic residues-Asp760 and Asp761 and hydrophobic interactions with neighbouring residues. Further, the physicochemical properties of the molecules were evaluated. These identified potential inhibitors warrant further experimental investigations before their acceptance as drug candidates for the treatment of the disease.

SUBMITTER: Gurung AB

PROVIDER: S-EPMC7708801 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The potential of Paritaprevir and Emetine as inhibitors of SARS-CoV-2 RdRp.

Gurung Arun Bahadur AB Ali Mohammad Ajmal MA Lee Joongku J Farah Mohammad Abul MA Al-Anazi Khalid Mashay KM

Saudi journal of biological sciences 20201202 2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a well-characterized therapeutic target which is a key player driving the viral replication and transcription machinery. The recent elucidation of the experimental structure of SARS-CoV-2 RdRp enzyme complexed with triphosphate form of Remdesivir (RTP) has opened an avenue for structure-based identification of potent inhibitors. Given the high mortality rate of the coronavirus disease 2019 (COVID- ...[more]

PMID: 33281478

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Project description:Vaccines are used as one of the major weapons for the eradication of pandemic. However, the rise of different variants of the SARS-CoV-2 virus is creating doubts regarding the end of the pandemic. Hence, there is an urgent need to develop more drug candidates which can be useful for the treatment of COVID-19. In the present research for the scientific hypothesis, emphasis was given on the direct antiviral therapy available for the treatment of COVID-19. In lieu of this, the available molecular targets which include Severe Acute Respiratory Syndrome Chymotrypsin-like Protease (SARS-3CLpro), Papain-Like Cysteine Protease (PLpro), and RNA-Dependent RNA Polymerase (RdRp) were explored. As per the current scientific reports and literature, among all the available molecular targets, RNA-Dependent RNA Polymerase (RdRp) was found to be a crucial molecular target for the treatment of COVID-19. Most of the inhibitors which are reported against this target consisted of the free amine group and carbonyl group which might be playing an important role in the binding interaction with the RdRp protein. Among all the reported RdRp inhibitors, remdesivir, favipiravir, and molnupiravir were found to be the most promising drugs against COVID-19. Overall, the structural features of this RNA-Dependent RNA Polymerase (RdRp) inhibitors proved the importance of pyrrolo-triazine and pyrimidine scaffolds. Previous computational models of these drug molecules indicated that substitution with the polar functional group, hydrogen bond donor, and electronegative atoms on these scaffolds may increase the activity against the RdRp protein. Hence, in line with the proposed hypothesis, in the present research work for the evaluation of the hypothesis, new molecules were designed from the pyrrolo-triazine and pyrimidine scaffolds. Further, molecular docking and MD simulation studies were performed with these designed molecules. All these designed molecules (DM-1, DM-2, and DM-3) showed the results as per the proposed hypothesis. Among all the designed molecules, DM-1 showed promising results against the RdRp protein of SARS-CoV-2. In the future, these structural features can be used for the development of new RdRp inhibitors with improved activity. Also, in the future lead compound DM-1 can be explored against the RdRp protein for the treatment of COVID-19.

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The potential of Paritaprevir and Emetine as inhibitors of SARS-CoV-2 RdRp.

Publications

The potential of Paritaprevir and Emetine as inhibitors of SARS-CoV-2 RdRp.

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