Identifying the Most Potent Dual-Targeting Compound(s) against 3CLprotease and NSP15exonuclease of SARS-CoV-2 from Nigella sativa: Virtual Screening via Physicochemical Properties, Docking and Dynamic Simulation Analysis

Abstract

Background: The outbreak of the coronavirus (SARS-CoV-2) has drastically affected the human population and caused enormous economic deprivation. It belongs to the β-coronavirus family and causes various problems such as acute respiratory distress syndrome and has resulted in a global pandemic. Though various medications have been under trial for combating COVID-19, specific medicine for treating COVID-19 is unavailable. Thus, the current situation urgently requires effective treatment modalities. Nigella sativa, a natural herb with reported antiviral activity and various pharmacological properties, has been selected in the present study to identify a therapeutic possibility for treating COVID-19. Methods: The present work aimed to virtually screen the bioactive compounds of N. sativa based on the physicochemical properties and docking approach against two SARS-CoV-2 enzymes responsible for crucial functions: 3CLpro (Main protease) and NSP15 (Nonstructural protein 15 or exonuclease). However, simulation trajectory analyses for 100ns were accomplished by using the YASARA STRUCTURE tool based on the AMBER14 force field with 400 snapshots every 250ps. RMSD and RMSF plots were successfully obtained for each target. Results: The results of molecular docking have shown higher binding energy of dithymoquinone (DTQ), a compound of N. sativa against 3CLpro and Nsp15, i.e., −8.56 kcal/mol and −8.31 kcal/mol, respectively. Further, the dynamic simulation has shown good stability of DTQ against both the targeted enzymes. In addition, physicochemical evaluation and toxicity assessment also revealed that DTQ obeyed the Lipinski rule and did not have any toxic side effects. Importantly, DTQ was much better in every aspect among the 13 N. sativa compounds and 2 control compounds tested. Conclusions: The results predicted that DTQ is a potent therapeutic molecule that could dual-target both 3CLpro and NSP15 for anti-COVID therapy.

Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach

“…Importantly, oleuropein has shown a strong hydrogen bonding with all these sub-pockets via THR26 (S2 catalytic center and S5), SER46 (S5), SER144 (S1), MET 165 (S1, S3, and S4), GLU166 (S1 and S4), ARG188 (S3 and S4), THR190 (S4), GLN192 (S4), and PHE 140 (S1). THR26 is part of the S2 catalytic center of 3CL pro and has been reported along with GLU166 and GLN189 as a crucial amino acid for 3CL pro targeting [ 10 , 38 , 39 ]. Even native ligand re-docking also suggested the involvement of GLU166, THR190, and PHE140 amino acid residues in hydrogen bonding.…”

“…In addition, olive leaves (whose major constituent is oleuropein) have been used as a co-therapy for COVID-19 patients [ 11 , 12 , 13 , 14 ]. It is noteworthy to mention that before selecting oleuropein for the present study the authors have explored dithymoquinone as a potent multi-target candidate against SARS-CoV-2 [ 10 ] and achieved some worthy outcomes on dithymoquinone analogues designed against neuro-COVID [unpublished data]. The neurological impact of COVID-19 is a well-established fact.…”

“…Hence, TLR-4 could be used as a targeting protein for neurological complications associated with COVID-19 [ 4 , 8 , 9 ]. Recently, our team has reported dithymoquinone as a potent dual-targeting candidate against SARS-CoV-2 [ 10 ]. However, in the present study, the focus is on neurological complications associated with SARS-CoV-2 infection, and the compound selected is oleuropein.…”

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID

“…Overall, the findings suggested that compound ( 4 ) remained inside the binding cavity of 3CL pro , TLR4 and PREP in a stable conformation. It is worth mentioning that the authors earlier screened out DTQ from Nigella sativa as the multi-targeting compound against COVID-19 [ 10 ]. In addition, DTQ has shown the potential to inhibit the viral-host interaction for the SARS-CoV-2 infection [ 47 ].…”

“…Thus, targeting TLR-4 may be effective [ 4 , 8 , 9 ]. It is to be noted that our team recently discovered dithymoquinone (DTQ) as a potent dual-targeting agent against SARS-CoV-2 [ 10 ]. Furthermore, different DTQ analogues were designed to explore their potency against 3CL pro (3-chymotrypsin like protease), TLR4 and PREP (prolyl oligopeptidases) in the current study.…”