Repurposing inhibitors for SARS-CoV2 main protease

SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Drug repurposing is a promising eld to provide potential short-term acceptable therapy for management of coronavirus till a specic anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Chemotherapeutic drugs and anti-retroviral drugs have shown potential binding as inhibitor. In-vitro and clinical trials required to establish nal fact.

Introduction SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Discovery of new drugs takes years of development and trials. The current pandemic situation makes it more di cult to arrange resources and conduct studies. Drug repurposing is a promising eld to provide potential short-term acceptable therapy for management of coronavirus till a speci c anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Choosing FDA-approved drugs for this study is important, so that any potential result obtained can be procured easily without delay.

Methodology
The procedure used in this study had been de ned in a previous study [1] and necessary permission was  For molecular docking, three-dimensional structures of 841 compounds were obtained from Zinc15 database [4]. The compounds constituted only those which were approved by FDA. This step was taken so as to facilitate easy availability after clinical trials.
6WTT structure constitutes three chains A, B and C. In order to obtain the active site of the receptor, Drug Discovery Studio software [5] was utilised to nd the interactions between the inhibitor and amino acids.
These amino acids would serve as the desired target in molecular docking.
PyRx software which includes within itself Autodock Vina and Open Babel was used for molecular docking [6][7] [8]. Since all three chains and their corresponding ligands were similar, only one chain was used as the target. The chain was extracted from the entire structure and it was cleared of all ligands and water molecules. The cleaned structure was converted into an Autodock macromolecule by addition of hydrogen atoms and partial charges. The ligand compounds from Zinc15 database were brought to the minimum energy con guration and were converted in Autodock ligands by using Open Babel. Exhaustiveness was set to 4 for faster computation. All the above operations were performed on a Windows 10 64-bit operating system. The entire docking took about 8 hours with 100% CPU utilization.

Results
The pocket site of the inhibitor was visualized and the following amino acids were found to be constituting the active site. Standard amino acid abbreviations are used. Numbers indicate their position in the sequence.   (Table 1) along with number of target amino acids it is bound to out of 8 mentioned above. It is rst sorted on the basis of decreasing order of interactions, then on the basis of increasing order of binding a nity up to -8.1 kcal/mol. The current therapeutic use has also been mentioned.

Ligand
Binding Affinity Their interactions are depicted below in gures 5-22 with amino acids of receptor chain (circles with sequence position of that amino acid).

Discussion
Literature review of the obtained drugs was conducted to establish any known studies proving its e cacy against coronavirus. Celsentri, saquinavir, nilotinib and risperdal had been reported to even inhibit SARS-CoV2 entry by targeting the receptor-binding domain [1]. Celsentri, lurasidone, paliperidone, argatroban, azelastine, dihydroergotamine, conivaptan, rolapitant and saquinavir have also been reported in other in-silico studies to inhibit protease [ MERS-CoV at 5.5 micromolar and SARS-CoV at 2.1 micromolar concentration [11]. Candesartan has been theoretically studied for treatment of SARS-CoV2 [12]. However, there were no relevant studies found for rest of the drugs linking them to coronavirus. These drugs must be pushed to in-vitro screening and clinical trials as treatment options or chemoprophylaxis.

Conclusion
In this study I have screened a large library of FDA-approved drugs and put forth promising results. At times of this ongoing pandemic, this study might contribute in the ght against coronavirus. The results though encouraging, must be tested in laboratory before proceeding with human trials and public use because of the limitations of in-silico approach. SARS-CoV2 main protease 6WTT tertiary structure visualised in UCSF Chimera [3] software. Ligands are marked in red.

Figure 2
Receptor chain is represented in lines. Target amino acids are highlighted in pink. Cuboid indicates the restricted search space including all target amino acids.