In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2.

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The interactions of Toll‐like receptor 4 (TLR4) with competitive inhibitors were investigated by a combined ligand‐based and target‐based approach. Firstly, the ligand‐based pharmacophore model of the reported TLR4 inhibitors was constructed by utilizing the common feature method, which included three hydrophobic groups and a hydrogen bond receptor. The Schrödinger software suite glide module was used to dock inhibitors with proteins and verify the importance of these four interaction points from the target level. Then, molecular dynamics, alanine scanning mutagenesis, and binding free energy calculation were used to identify the key amino acids in the binding mode. In addition, blind docking proved that the TLR4 inhibitor does not bind to TLR4 itself like other TLR family proteins. Based on this, we also screened a class of sesquiterpene coumarins which possibly have TLR4 inhibitory activity and will conduct a detailed study later. Together, this study revealed the interactions between TLR4 protein and its competitive inhibitors, which shed light on better access for developing its novel inhibitors.