In Silico Study of Curcumin and Folic Acid as Potent Inhibitors of Human Transmembrane Protease Serine 2 in the Treatment of COVID-19

Abstract

Background. Human transmembrane protease 2 (TMPRSS2) protein is essential for priming spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with human angiotensin-converting enzyme 2 (ACE2) surface receptor to facilitate viral invasion into host human cell through ACE2 receptor. Impeding TMPRSS2 protein activity is currently a preferred choice of the treatment of coronavirus disease 2019 (COVID-19) which is caused by SARS-CoV-2. Curcumin and folic acid are potential candidates for inhibiting TMPRSS2. Objective. The present study aimed to demonstrate the inhibitory activities of curcumin and folic acid, along with known human serine protease inhibitors such as nafamostat and camostat, on TMPRSS2. Methods. Curcumin and folic acid, along with nafamostat and camostat, were docked on a modeled human TMPRSS2 protein 3D structure. Nafamostat and curcumin interactions with targeted TMPRSS2 protein were identical whereas camostat and folic acid displayed similar interactions. Results. The hydrogen bond (H-bond) energies of docked curcumin, folic acid, nafamostat, and camostat were −19.86 kJ/mol, −17.63 kJ/mol, −10.53 kJ/mol, and −14.41 kJ/mol, respectively. Higher H-bond energies could strengthen protein-ligand interactions. Our results showed binding site similarities between curcumin and nafamostat as well as folic acid and camostat. Conclusion. The current in silico simulation suggested that curcumin and folic acid displayed binding poses with TMPRSS2 which are similar to nafamostat and camostat. Therefore, curcumin and folic acid could emerge as potential drug candidates to control COVID-19.

Curcumin as a Potential Treatment for COVID-19

“…The transmembrane protein serine protease 2 (TMPRSS2) facilitates the entry of SARS-CoV-2 from the spike protein (Hoffmann et al, 2020). In silico analyses focusing on TMPRSS2 showed that curcumin forms four hydrophobic interactions and an H-bond with TMPRSS2 (Motohashi et al, 2020). These findings corroborated results of in vitro studies where curcumin treatment led to the downregulation of TMPRSS2 in prostate cancer cells (Zhang et al, 2007;Thangapazham et al, 2008).…”

Curcumin and turmeric extract inhibit SARS-CoV-2 pseudovirus cell entry and spike-mediated cell fusion

“…Based on in silico data, curcumin can interact with SARS-CoV-2 Spike RBD (Shanmugarajan et al, 2020), hACE2 (Subbaiyan et al, 2020), and TMPRSS2 as well (Motohashi et al, 2020). These data align with our results that curcumin inhibited PSV entry and syncytia formation.…”

“…In silico analysis showed that curcumin has a high affinity for binding to the spike glycoprotein through the formation of six hydrogen bonds (Maurya et al, 2020), thus, curcumin has the potential to prevent the binding of the viral spike protein to the ACE2 receptor and inhibit the initiation of the host cell infection process. Moreover, curcumin forms four hydrophobic interactions via hydrogen bonds with TMPRSS2, which may inhibit cellular entry through the cell fusion mechanism (Motohashi et al, 2020).…”

The impact of COVID-19 on populations living at high altitude: Role of hypoxia-inducible factors (HIFs) signaling pathway in SARS-CoV-2 infection and replication

“…In a model of acute lung injury, treatment with curcumin was reported to increase PaO 2 , to decrease pulmonary oedema and to improve lung function ( Cheng et al, 2018 ). At the molecular level, among other antiviral mechanisms ( Rattis et al, 2021 ), curcumin has been reported to show high affinity for both SARS-CoV-2 spike (S) glycoprotein and its cellular receptor, ACE2 and to bind TMPRSS2, suggesting a capacity to block viral attachment to target cells ( Maurya et al, 2020 ; Motohashi et al, 2020 ; Shanmugarajan et al, 2020 ). Curcumin is also thought to interfere with endosomal acidification, an essential step in the SARS-CoV-2 replication cycle ( Vishvakarma et al, 2011 ).…”