ABSTRACT
COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74% identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. The crystal structure of the SARS-CoV (6CRV: full length S protein) and SARS-CoV-2 Spike proteins (6M0J: Receptor binding domain, RBD) was used to determine potential small molecule inhibitors. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -10.98 to -5.12 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-demethoxycurcumin with: ΔG = -10.98 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors. However, further research is necessary to investigate the ability of these compounds as viral entry inhibitors.Communicated by Ramaswamy H. Sarma.
Subject(s)
Curcumin , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Curcumin/analogs & derivatives , Curcumin/pharmacology , Humans , Protein Binding , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , COVID-19 Drug TreatmentABSTRACT
The present study was designed to evaluate the protective effect of fisetin against rotenone induced toxicity in SH-SY5Y neuroblastoma cellular model of Parkinson's disease (PD). SH-SY5Y neuroblastoma cells were treated with fisetin (5µM) 2 hr prior to being treated with rotenone (100 nM). Following the exposure of SH-SY5Y cells to rotenone, there was marked decreased cell viability, increased oxidative stress, activation of caspase-3 and apoptosis (dual staining, expressions of pro-apoptotic and anti-apoptotic indices). However pretreatment with fisetin significantly and dose-dependently alleviated rotenone induced cytotoxicity and oxidative stress in SH-SY5Y cells. Moreover, fisetin attenuated rotenone induced toxicity by down-regulating Bax, caspases-3 protein expression and up-regulating protein expression of Bcl-2, p38/JNK-MAPK and PI3K, Akt, GSK-3ß pathways. Collectively, these results suggest that fisetin could prevent the rotenone-induced neurotoxicity via various signaling pathways.