Abstract
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiologic agent of the current pandemic of corona virus disease 2019 (COVID-19) that has inflicted the loss of thousands of lives worldwide. The coronavirus surface spike (S) glycoprotein is a class I fusion with a S1 domain which is attached to the human angiotensin converting enzyme 2 (ACE2) receptor, and a S2 domain which enables fusion with the host cell membrane and internalization of the virus. Curcumin has been suggested as a potential drug to control inflammation and as a potential inhibitor of S protein, but its therapeutic effects are hampered by poor bioavailability. We performed a molecular docking and dynamic study using 94 curcumin analogues designed to have improved metabolic stability against the SARS-CoV-2 spike protein and compared their affinity with curcumin and other potential inhibitors. The docking analysis suggested that the S2 domain is the main target of these compounds and compound 2606 displayed a higher binding affinity (-9.6 kcal mol-1) than curcumin (-6.8 kcal mol-1) and the Food and Drug Administration (FDA) approved drug hydroxychloroquine (-6.3 kcal mol-1). Further additional validation in vitro and in vivo of these compounds against SARS-CoV-2 may provide insights into the development of a drug that prevents virus entry into host cells.
Highlights
The SARS-associated coronavirus (SARS-CoV) is the causative agent of severe acute respiratory syndrome (SARS), which emerged as an epidemic from 2002 to 2003
As many compounds used in simulation have a large number of torsions, the results obtained in the AutoDock Vina program may be more suitable for these simulations than those obtained in AutoDock
We have shown by molecular docking that a series of curcumin analogues with a mono-keto moiety have the potential to inhibit SARS-CoV-2 spike protein interaction with the host receptor
Summary
The SARS-associated coronavirus (SARS-CoV) is the causative agent of severe acute respiratory syndrome (SARS), which emerged as an epidemic from 2002 to 2003. Pathogenicity) at the active site of S proteins.[21] Among 33 molecules studied, a natural compound (rutin) showed greater efficiency in binding to the active site of the SARS‐CoV-2 protease, than a control antiviral drug (ritinovir), an antiprotozoal drug (emetin) and hesperidin which is a natural compound.[22] Another natural compound studied for COVID-19 treatment is curcumin [(1E,6E)-1,7-bis(4-hydroxy3‐methoxyphenyl)-1,6-heptadiene-3,5-dione], a dietary phytochemical constituent of turmeric powder derived from the rhizomes of Curcuma longa.[23] It has several benefits in controlling inflammation,[24] which is a common reaction caused by SARS-CoV-2.25 In addition, curcumin has been reported to have a good binding affinity and efficient pharmacokinetic parameters, suggesting its use as a potential inhibitor of the S protein.[26,27] On the other hand the therapeutic effects of curcumin are hampered by its poor absorption after ingestion, quick degradation under physiological pH conditions, as well as rapid metabolism and elimination.[23]. We found that compound 2606 has potential as an inhibitor of the S2 domain and could be explored to inhibit the fusion of SARS-CoV-2 and host cell membranes, which are a potential therapeutic target for micromolecules
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