Inhibitory capacity of chloroquine against SARS-COV-2 by effective binding with angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies
“…The difference could be because of use of different software or due to the use of ACE2-spike crystal complex for HCQ docking in their studies. Additionally, the site of chloroquine binding to ACE2 found in recent calculations [ 50 ] is also found in our calculations on HCQ, but with a lower ranking. Fig.…”
Section: Resultssupporting
confidence: 83%
“…Earlier studies have sought to repurpose drugs targeted towards host molecules ACE2, quinone reductase and viral molecules nsp12 RNA polymerase, nsp3 protease, nucleocapsid, spike, capping machinery nsp14/nsp16 etc. [ [47] , [48] , [49] , [50] ] and these are all different, except ACE2, from the molecules we have found as targets for docking in the present study. Further, the target proteins identified in this study are shown experimentally to play critical roles in the SARS-COV-2 infection process [ 15 , 44 , 45 , 51 ] and therefore, are appropriate targets for inhibition by HCQ [ 44 , 52 , 53 ].…”
COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed a global health emergency. Repurposing of existing drugs can be a rapid and effective strategy to fight the infection. Clinical trials have reported reduction or elimination of viral load when patients were treated with the anti-malarial drug Hydroxychloroquine (HCQ). To understand the molecular mechanism of action for effective repurposing of this drug we have carried out
in silico
docking and dynamics studies on complexes between HCQ and target proteins, which were identified through both literature survey and structural similarity searches in databases of small molecule – protein complexes. The proteins identified as binding HCQ are: Angiotensin Converting Enzyme 2 (ACE2), α7 nicotinic AcetylCholine Receptor (α7 nAChR), α1D-adrenergic receptor (α1D-AR), Histamine N- Methyl Transferase (HNMT) and DNA gyrase/Topoisomerase III β (Top3β). The majority of these proteins are novel and have not been used before, in docking studies. Our docking and simulation results support action of HCQ both at the entry and post-entry stages of SARS-CoV2 infection. The mechanism of action at the entry stage is through blocking the virus-binding sites on the two receptors, ACE2 & α7 nAChR, by binding directly at those sites. Our computational studies also show that the action of HCQ at the post-entry stage is to prevent both viral replication and generation of ‘cytokine storm’ by inhibiting host Top3β enzyme and α1D-AR, respectively. Binding of HCQ to HNMT is not a desired binding, and therefore this should be reduced during repurposing of HCQ.
“…The difference could be because of use of different software or due to the use of ACE2-spike crystal complex for HCQ docking in their studies. Additionally, the site of chloroquine binding to ACE2 found in recent calculations [ 50 ] is also found in our calculations on HCQ, but with a lower ranking. Fig.…”
Section: Resultssupporting
confidence: 83%
“…Earlier studies have sought to repurpose drugs targeted towards host molecules ACE2, quinone reductase and viral molecules nsp12 RNA polymerase, nsp3 protease, nucleocapsid, spike, capping machinery nsp14/nsp16 etc. [ [47] , [48] , [49] , [50] ] and these are all different, except ACE2, from the molecules we have found as targets for docking in the present study. Further, the target proteins identified in this study are shown experimentally to play critical roles in the SARS-COV-2 infection process [ 15 , 44 , 45 , 51 ] and therefore, are appropriate targets for inhibition by HCQ [ 44 , 52 , 53 ].…”
COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed a global health emergency. Repurposing of existing drugs can be a rapid and effective strategy to fight the infection. Clinical trials have reported reduction or elimination of viral load when patients were treated with the anti-malarial drug Hydroxychloroquine (HCQ). To understand the molecular mechanism of action for effective repurposing of this drug we have carried out
in silico
docking and dynamics studies on complexes between HCQ and target proteins, which were identified through both literature survey and structural similarity searches in databases of small molecule – protein complexes. The proteins identified as binding HCQ are: Angiotensin Converting Enzyme 2 (ACE2), α7 nicotinic AcetylCholine Receptor (α7 nAChR), α1D-adrenergic receptor (α1D-AR), Histamine N- Methyl Transferase (HNMT) and DNA gyrase/Topoisomerase III β (Top3β). The majority of these proteins are novel and have not been used before, in docking studies. Our docking and simulation results support action of HCQ both at the entry and post-entry stages of SARS-CoV2 infection. The mechanism of action at the entry stage is through blocking the virus-binding sites on the two receptors, ACE2 & α7 nAChR, by binding directly at those sites. Our computational studies also show that the action of HCQ at the post-entry stage is to prevent both viral replication and generation of ‘cytokine storm’ by inhibiting host Top3β enzyme and α1D-AR, respectively. Binding of HCQ to HNMT is not a desired binding, and therefore this should be reduced during repurposing of HCQ.
“…Till now, it is not clear that whether these COVID-19 vaccines can protect against the infection from these new SARS-CoV-2 variants or not (Fontanet et al 2021;Mascola et al 2021). Recently, name of the few drugs e.g., Remdesivir, Hydroxychloroquine, Chloroquine are the topic of discussion to researchers but none of these are potentially efficient against this deadly virus (Baildya et al 2020(Baildya et al , 2021aElfiky 2020;Khan et al 2021;Mandal et al 2021).…”
Outbreak of Coronavirus (SARS-CoV-2) has thrown a big challenge to the globe by snatching millions of human lives from the world. In this study, inhibitory efficiency of ten anti-HIV compounds from different Indian medicinal plant parts have been virtually screened against Mpro, PLpro and RdRp proteins of SARS-CoV-2. The molecular docking study reflected that among these compounds, Proptine (PTP) has the highest binding affinity for the three cases. Introduction of PTP molecules within the binding pocket of these proteins showed a large structural and conformational changes on the structure of proteins which is revealed from molecular dynamics (MD) simulation studies. RMSD, RMSF and analysis of thermodynamic parameters also revealed that PTP makes a huge impact on the structures of the respective proteins which will pave an opportunity for doing advanced experimental research to evaluate the potential drug to combat COVID-19.
“…Recently a number of drugs are reported viz. Remdesivir [ 7 , 10 ], Hydroxychloroquine (HCQ) [11] , Chloroquine (CQ) [13] , and natural products of different pant resources [14] , [15] , [16] , [17] , [18] and other RNA virus drugs [19] but none of these are particularly effective for this virus. Hydroxychloroquine in combination with azithromycine was also applied for the treatment of COVID-19 [20] .…”
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