Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations.

Rafat Zrieq,Emira Noumi,Shadi Sulaiman,Iqrar Ahmad,Munazzah Tasleem,Fahad D Algahtani,Harun Patel,Adel Kadri,Marcello Iriti,Kaïss Aouadi,Mejdi Snoussi,Mohd Saeed

doi:10.3390/ijms221910693

Abstract

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

Highlights

The current contagious pandemic of the novel severe acute respiratory syndrome coronavirus 2 named SARS-CoV-2, is a viral pneumonia and a threat to global public health [1,2]
Patchouli alcohol is one of the important compounds isolated from the essential oil of Pogostemon cablin, in parallel with tomatidine as a glycoalkaloid and an agly-cone metabolite of tomatidine which is largely present in high amount in unripe tomato and were tested here, for the first time for their potential effect as anti-SARS-CoV-2, using in silico methods
(SARS-CoV-2) inhibitors were used for blind docking analysis of the known drugs, tomatidine and patchouli alcohol

Summary

Introduction

The current contagious pandemic of the novel severe acute respiratory syndrome coronavirus 2 named SARS-CoV-2, is a viral pneumonia and a threat to global public health [1,2]. The SARS-CoV2 is a single-stranded positive-sense RNA genome of size 29.7 kb [3]. It was composed of Spike glycoprotein (S), Envelope protein (E), Membrane protein (M) and Nucleocapsid protein (N). PLpro is essential for replication/transcription complex (RTC) formation and is responsible for release of NSP1, NSP2 and NSP3 from the N-terminal region of pp1a and 1ab [11]. Their inhibition can block these processes and prevent the viral infection. NSP15 protein acts as an endoribonuclease and preferentially cleaves 30 of uridylates through a ribonuclease A

Methods

Results

Conclusion