Molecular Docking and Molecular Dynamics Aided Virtual Search of OliveNet™ Directory for Secoiridoids to Combat SARS-CoV-2 Infection and Associated Hyperinflammatory Responses

Abstract

Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARS-CoV-2 spike (S) protein-ACE-2 interface; Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (Mpro). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-Mpro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of Mpro with DMO and, thus, its inhibition. The docking predicted IC50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and Mpro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection.

Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease

“…It is a theoretical simulation to study the interaction between ligand and receptor and predict their binding mode and affinity [ 47 ]. Moreover, the computational docking is accompanied by FRET assay, which is an effective mean of exploring whether the molecules could be inactive the enzymatic protein and is regarded as an important technology in the development of anti-CoV compounds [ 45 ]. Thus, our FRET results ( Figure 4 ) confirmed the binding of hypericin onto PEDV 3CLpro ( Figure 3 and Figure S2 ), leading to an inhibitory effect.…”

“…We have previously shown that hypericin inhibits γ-CoV through the reduction of viral-induced ROS and apoptosis, which in turn inhibited the viral replication [23]. However, several molecular docking assays showed that hypericin binds to the main intracellular replication enzyme (3CLpro) of SARS-CoV-2, indicating that hypericin has the potential to target β-CoV 3CLpro [8,9,45]. It remained to explore if hypericin could serve as a viral inhibitor for PEDV and TGEV as 3CLpro sequences and structures in CoV are highly conserved shared 51% averaged sequence identity (Figure 2, Figure 5 and Figure S1) [7], and they are involved in viral intracellular replication through the selfcleavage of viral pp1a and pp1ab.…”

Virtual screening and in vitro validation of natural compound inhibitors against SARS-CoV-2 spike protein

“…Using this information, we aimed to identify natural compounds with anti-SARS-CoV-2 activity using a combined molecular docking and in vitro approach. Most docking studies screening natural compounds against the spike protein have screened only a small number of ligands (≤200) and focus on the computational aspect alone [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] . Even larger-scale studies do not include experimental validation [41] , [42] , [43] .…”

Green and Non‐conventional Extraction of Bioactive Compounds from Olive Leaves: Screening of Novel Natural Deep Eutectic Solvents and Investigation of Process Parameters

“…Regarding these properties, olive leaf components have been under research for their potential anti-viral effect against SARS-CoV-2 that causes Coronavirus disease . Lately, remarkable results were presented on the blockage of the SARS-CoV-2 spike protein-ACE-2 interface by oleuropein dimer and dihydro oleuropein [11]. Additionally, demethyloleuropein was reported to block SARS-CoV-2 main protease [11].…”

“…Lately, remarkable results were presented on the blockage of the SARS-CoV-2 spike protein-ACE-2 interface by oleuropein dimer and dihydro oleuropein [11]. Additionally, demethyloleuropein was reported to block SARS-CoV-2 main protease [11]. On the other hand, oleuropein, quercetin, luteolin-7-glucoside, apigenin-7-glucoside, catechin and epicatechin-gallate were reported to be investigated as the potential inhibitor of Covid-19 main protease [12].…”