Drug Repurposing of Approved Drugs Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine and Ergotamine for Combating COVID19

Drug is one the most promising approaches for Many are available with in silico drug repurposing but the majority of them engrossed on a single target. The present study aimed at screening the approved against Covid19 protein and extract the combination of operational comprehensively. A total of 1735 drug molecules against all COVID19 protein structures and sequential screening recognize the better potential of anti-HCV drugs over anti-HIV drugs. The study designated Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine Ergotamin as promising drug candidates for covid19 treatment. The computational analysis also reveled the better potential of proposed drugs over the currently used drug combination for COVID19 drugs. Abstract Aims: Pneumonia of unknown cause detected in Wuhan, China was first reported to the WHO Country Office in China on 31 December 2019. The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020. Currently, there is no Vaccine against COVID-19 pandemic and infection is spreading worldwide very rapidly. The present study aimed to meet the exigent requirement of practicable COVID19 drug treatment with a computational multi-target drug repurposing approach. Main methods: Many reports are available with in silico drug repurposing. However, the majority of them engrossed on a single target. In the present study, 1735 FDA approved drugs screened with molecular docking approach against Covid19 protein and extracts the drug combination targeting COVID19 proteins comprehensively. Key findings: The study designated Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine, and Ergotamine as promising drug candidates for covid19 treatment. The computational analysis also revealed the better potential of the proposed drug combination over the currently used drugs for COVID19 treatment. Significance: The anticipated drug combination is acting on both non-structural and structural proteins therefore, it can be able to reduce the COVID19 infection process and also reduce viral multiplication. Moreover, the drugs are safe and well-known so it can be rapidly explored further for the COVID19 drug discovery process.


Introduction
The World Health Organization announced in February 2020 that COVID-19 is the official name of the disease. World Health Organization chief Tedros Adhanom Ghebreyesus explained that CO stands for corona, VI for virus and D for disease, while 19 is for the year that the outbreak was first identified; 31 December 2019 [1]. Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) previously referred to as the 2019 novel coronavirus (2019-nCoV) [2]. In 2019 at Wuhan, the capital of Hubei, China, the disease was first reported and then it spread worldwide, resulting in the 2019-20 coronavirus pandemic [3,4].
At present, there are no clinically proven vaccines and medicines for COVID-19 prevention and treatment as per U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) [5]. On an interactive web-based dashboard to track COVID-19 in real-time as on April 19, 2020, in the entire world more than 200 countries/territories are having 2.3 Million confirmed cases and 1,61,283 deaths worldwide and more than 50000 increase daily reported since March 26, 2020 [6,7].
Recovery observed in patients of Covid19 treated with the mixture of Anti-HIV drugs like Libonavir & Ritonavir, Anti-SARS drugs Oseltamivir and Anti-malarial drug Chloroquine in India (Wadhawan, 2020). In South Korea, human MERS-CoV successfully revokes the viral clearance using a combination of Lopinavir/Ritonavir (LPV/RTV) (Anti-HIV drugs) pegylated interferon and ribavirin [8]. Still, the treatment with anti-HIV drugs is a mystery for the Patients and Researchers as well [9].
Recently, diverse computational approaches explored for screening the drug molecules for COVID19 treatment. Molecular docking of Lopinavir, Darunavir and Ritonavir reported against the modelled structure of COVID19 proteases, coronavirus endopeptidase C30 (CEP_C30) and papain-like viral protease (PLVP) [10]. MM-PBSA-WSAS (Molecular dynamics simulations followed by binding free energy calculations using an endpoint method) employed for Fast Identification of Possible Drug against COVID-19 protease [11]. Anti-HCV drugs, Sofosbuvir, IDX-184, Ribavirin, and Remidisvir reported promising drug candidates with a docking approach against modelled COVID-19 RNA dependent RNA polymerase (RdRp) [12]. Hirokawa et al., (2020) identified one hundred and several dozen potentially candidate drugs for 3CL protease inhibitors, which are already approved as antiviral, HIV protease inhibitors, antibacterial or antineoplastic agents with in silico docking-based screening approach, which combines molecular docking with a protein-ligand interaction fingerprint (PLIF) scoring method.
Many other reports are also available with in silico drug repurposing but the majority of them engrossed on a single target. The present study designed for docking FDA approved Drugbank compounds with molecular weight less than 700 against all COVID-19 experimentally and computationally generated protein structure.

Data Analysis
The Binding energy for each drug ligand exported for analysis from the Autodock Vina v4.2 software and need-based analyses performed manually using python script and excel software. Drug target interaction analysed with Ligplot + [22].

Results
Drug repurposing study for FDA approved 1735 drug molecules < 700 MW included in the present study. The molecular docking accomplished against a total of 24 modeled proteins and 3 PDB structures followed by seven-stage screening to determine the best combination for COVID19 treatment.
In    The binding energy of selected 35 compounds graded in five grades displaying dark green, light green, yellow, orange and red for easy comparison. Concerning anti-COVID19 activity against single and multiple target analysis, the best results obtained for 8 drugs from anti-HCV followed by 7 anti-HIV and 3 currently clinically used drugs. In addition to that, 1 drug from an anti-inflammatory and anti-migraine group also had a good docking score. The overall analysis presented the comparatively better scoring of the selected drug in this study over currently clinically applied drugs for COVID19 treatment (Figure 1) To narrow down the number of drug combinations and removing drug acting on the same target binding energy replaced with docking rank. Based on dock rank 10 drugs selected for further analysis (Figure 2). To reduce the drug for treatment and avoid duplication, the drug acting on the same target was removed. Consequently, the combination of Elbasvir, Ledipasvir, Paritaprevir, Velpatasvir, Antrafenine Ergotamine drug figured out as a potential cocktail for COVID19 treatment ( Figure 3).

Comparative binding interaction of drugs against HCV and COVID19
To analyse the comparative binding interaction with HCV targets for anti-COVID19 receptors, three targets of HCV NS3 Helicase, NS5B RNA-dependent RNA polymerase and NS3/4A S168A protease docked against 26 potential drugs along with known inhibitors. The result indicated, Chloroquine antiplasmodial drug computationally significant for three HCV receptors but the same is less significant for COVID19 (Figure 4). Similarly, anti-HIV drugs Dolutegravir and Maraviroc had considerable binding against HCV targets but less potential with COVID19 receptors. Conversely, Elbasvir, Ledipasvir reacted with related potential against Helicase, RdRp and Protease from both virus HCV and COVID19. This projected the potential of anti-HCV drugs for inhibition of the COVID19 virus.
While ergotamine used in the present study proposes significant binding against all three COVID19 proteins but no promising binding evident with HCV. This suggests the presence of a specific binding site present in COVID19 which might be absent in HCV.

Discussion
The earlier report of drug repurposing mainly focused on a single target option we represented the Ledipasvir is an inhibitor of the Hepatitis C Virus (HCV) Non-Structural Protein 5A (NS5A) [23].
This protein is crucial for viral RNA replication and assembly of HCV virions. Ledipasvir and Velpatasvir were reported promising in one of the recent studies in virtual screening [24]. Clinical trials against anti-HCV suggest the Ledipasvir treatment significantly improves the patients within one to twelve weeks [25,26].
Similarly, Velpatasvir acts as a defective substrate for NS5A (Non-Structural Protein 5A) sharing a similar function as Ledipasvir. The preclinical study shown the patient having an infection of HCV genotype 1 to 6 can be treated with Velpatasvir [27].
Elbasvir was primarily used for the treatment of HCV. However, some trials are also carried out for using Elbasvir in the treatment of COVID19 [28]. Paritaprevir reported as an inhibitor of COVID19 Protease [29]. No reports are available for anti-COVD19 effectively of Antrafenine and Ergotamine.
As COVID19 and HCV both are positive-strand RNA viruses and possess a similar mechanism for the creation of viral protein in the host cells. The drugs effective against HCV can have a similar mode of inhibition for the viral protein synthesis mechanism. The lesser effectively of the anti-HIV drugs are due to differential mechanism for synthesis of viral protein. Recently,  reported the clinical study using HCV protease inhibitor Danoprevir to treat naive and experienced COVID-19 patients which are supportive of our hypothesis of using the anti-HCV drugs for anti-COID19 treatment.

Conclusion
There is an urgent need for anti-COVID-19 drugs to address the global medical emergency. Several drugs are currently employed with empirical clinical knowledge along with some contradictions.
Many drug repurposing reports are available but those are mainly concentrated on a single target. The present study directed with a holistic approach of targeting multiple COVID19 proteins with a mixture of FDA approved drugs. The proposed blend drugs include Elbasvir, Ledipasvir, Paritaprevir, and Velpatasvir which currently used for HCV treatment. Inclusion anti-inflammatory Antrafenine and anti-migraine Ergotamine drugs can be effective for dual action of inflammation reduction and COVID19 inhibition. The anticipated combination of drugs acting on both non-structural and structural proteins therefore, can be able to reduce the COVID19 infection process and also reduce viral multiplication. The present study can be immediacy explore further by medical, pharm and research experts effectively to find out the best strategy for anti-COVID19 treatment.