key: cord-0875588-38frnlu8
authors: Deshpande, Rujuta R.; Tiwari, Arpita Pandey; Nyayanit, Narendra; Modak, Manisha
title: In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2
date: 2020-08-03
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173430
sha: 10066048c64d6e0f510a99476d41f0ef6abf6a1d
doc_id: 875588
cord_uid: 38frnlu8

SARS-CoV-2 has devastated the world with its rapid spread and fatality. The researchers across the globe are struggling hard to search a drug to treat this infection. Understanding the time constraint, the best approach is to study clinically approved drugs for control of this deadly pandemic of COVID 19. The repurposing of such drugs can be supported with the study of molecular interactions to enhance the possibility of application. The present work is a molecular docking study of proteins responsible for viral propagation namely 3Clpro, Nsp10/16, Spike protein, SARS protein receptor binding domain, Nsp 9 viral single strand binding protein and viral helicase. The protein through virus enters the host cell-human angiotensin-converting enzyme 2 (ACE2) receptor, is also used as a target for molecular docking. The docking was done with most discussed drugs for SARS-CoV-2 like Ritonavir, Lopinavir, Remdesivir, Chloroquine, Hydroxychloroquine (HCQ), routine antiviral drugs like Oseltamivir and Ribavirin. In addition, small molecules with anti-inflammatory actions like Mycophenolic acid (MPA), Pemirolast, Isoniazid and Eriodictyol were also tested. The generated data confirms the potential of Ritonavir, Lopinavir and Remdesivir as a therapeutic candidate against SARS-CoV-2. It is observed that Eriodictyol binds to almost all selected target proteins with good binding energy, suggesting its importance in treatment of COVID 19. Molecular interactions of Ritonavir, Lopinavir and Remdesivir against SARS-CoV-2 proteins enhanced their potential as a candidate drug for treatment of COVID-19. Eriodictyol had emerged as a new repurposing drug that can be used in COVID-19.

represents proteins along with their PDB ID and structure which were used as 116 targets for molecular docking. These proteins play an important role in viral replication and virus 117 entry. Table 2 gives the details of ligands which were selected for molecular docking. Traditional 118 structure-based method of molecular docking was done because of availability of 3D structures 119 of SARS-CoV-2 virus. Table 3 A and 3 B shows molecular docking data represented in terms of 120 binding energy (ΔG) in Kcal/mole for selected viral target proteins ( show that all these compounds are binding to all viral proteins as well as human ACE 2 to some 123 extent. Different ligands are showing highest binding against different proteins and this data are 124 presented in Table 4 . It was observed that Ritonavir is giving efficient binding energy for Nsp16, 125 6W75D, 6VSBC and 2GHV whereas Remdesivir is more active against 6M03, 6LU7, 6VSBB, 126 6W75B. It was observed that Lopinavir shows a highly efficient binding with key viral proteins 127 like 6Y84, 6W4B, 6VSBA, 6VXS and ACE 2 receptor protein 6M18B and 6M18D. Out of the 128 small molecules tested here, Eriodictyol has high binding efficiencies against all selected 129 proteins. Nevertheless, Pemirolast also shows high binding efficiencies against 6M03 and 6W4B. ligand and amino acids present in active site of that protein is shown in Table 5 . It was observed 140 that in case of 6Y84 almost all drugs which are binding to this protein are binding to 3 amino 141 acids from active site GLN127, GLU290 and PHE 191 Among all these ligands, Eriodictyol has the highest potential to be repurposed as an antiviral 165 against SARS-CoV-2 since it is binding to 6VXS, 6VSB C, 6W75D along with 6Y84. Such drugs are already approved for their safety and it's ADME properties are already known 178 (Smith and Smith, 2020). Unavailability of protein structures of SARS-CoV-2 was one of the 179 major hurdles to curate the huge bulk of antivirals for studying molecular interaction. As 3D 180 structures of many proteins from SARS-CoV-2 are reconstructed and deposited in protein databases, we decided to use these structures to study the molecular interactions of known 182 antivirals. 183 We have selected viral proteins which are important for viral replication and viral entry to Lopinavir and Remdesivir are also binding with 6M18 i.e. ACE-2 receptor of human cell but this 213 binding is not at active site. As all three drugs are binding to viral main protease and ACE 2, 214 these drugs might be the important candidates for repurposing if mechanism of action is known. Montaner, 2011). Pulmonary discomfort is one of the important symptoms in COVID-19. 220 Pemirolast, is a mast cell stabilizer used in anti-allergy medication for treating chronic asthma 221 (Kemp et al., 1992) . Eriodictyol, is a flavanone found in Yerba Santa a plant native to North 222 America and is a traditional herbal remedy used for asthma and treating common colds (Bown 223 and America, 1995). Asthma drugs may act locally to get control over the respiratory system.

This will reduce the hospitalization time and improve the general health of the patient. Therefore, 225 these drugs were tested to check their potential role in suppressing the viral replication via 226 interacting with viral proteins. One interesting observation here is that the drug Eriodictyol is binding with all selected proteins with the binding energy between -6.7 Kcal/mol and 8.8 (Table 5 ). This strong interaction may affect the activity of enzyme. Eriodictyol is binding to 

Drug repurposing is the best approach for finding out solution for treatment of novel 275 coronavirus infection. If the targets and mechanism of action of these drugs are known then 276 formulating treatment would be easier. Therefore, the extensive work carried out in this study to 2 Lopinavir -7.3 -5.9 -9.9 -6.4 -6.9 -6.2 -6.6 -7.1 -7.9 -6.9 -7.3 -6.5 -6.9

3 Remdesivir -7.8 -7.2 -9.4 -6.2 -6.5 -6.8 -6.2 -6.9 -6.9 -6.9 -7.6 -7 -6.9

4 Oseltamivir -6.1 -5.2 -6.6 -4.3 -5.3 - 

Mycophenolic acid

Mycophenolic acid (MPA) 6Y84 (Mpro/3CLpro (Main protease of SARS-CoV-2) Yes

Chloroquine 6Y84 (Mpro/3CLpro (Main protease of SARS-CoV-2) Yes

Hydroxychloroquine (HCQ) 6Y84 (Mpro/3CLpro (Main protease of SARS-CoV-2) Yes

Pemirolast 6Y84 (Mpro/3CLpro (Main protease of SARS-CoV-2)

6VXS (ADP ribose phosphatase of NSP3 from SARS CoV-2) Yes

Eriodictyol 6Y84 (Mpro/3CLpro (Main protease of SARS-CoV-2)

6VXS (ADP ribose phosphatase of NSP3 from SARS CoV-2)

Complex from SARS-CoV-2) Yes