A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

Abstract

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.

Spectroscopic investigation and structural simulation in human serum albumin with hydroxychloroquine/Silybum marianum and a possible potential COVID‐19 drug candidate

“…[41][42][43] This finding was consistent PubChem, provided valuable insights into the binding interaction between the HCQ/SM mixture and its affinity toward HSA. [15,[44][45][46][47][48][49][50] 2.6 | Molecular docking with SARS-CoV-2 virus as a receptor (PDB ID: 6LU7 and 7TLL) protein…”

“…The individual molecules are found to be within the hydrogen bonding range of Trp 214 residue subdomains IB, IIA, and IIIA, according to docking experiments. [14] Also, Lan-Yi Hu and collaborators reported the affinity behavior of chloroquine and HCQ with HSA using computer simulation and the multispectral approach of biochemistry [5,15] Several drugs, including remdesivir, favipiravir, dexamethasone, and HCQ, have exhibited therapeutic efficacy in early clinical treatment of patients with COVID-19. These medications have demonstrated the ability to rapidly reduce viral load using various mechanisms.…”

“…Additionally, certain quinoline derivatives like saquinavir and elvitegravir have been suggested as potential inhibitors of COVID-19. [7,8,14,15] Azeem's study, [16] focusing on the interaction between HCQ and HSA, presents a detailed investigation into the interaction between HSA and HCQ. Conversely, prior research has underscored potential synergistic effects and interactions arising from HCQ's combination with other medications and herbal supplements, indicating the imperative to investigate their coadministration for possible therapeutic advantages or adverse outcomes.…”

The effect of various compounds on the COVID mechanisms, from chemical to molecular aspects

“…Regulation of spike-ACE2 attachment by binding an NMA at a site other than the ACE2 active site is a promising strategy to design novel drugs for COVID-19 treatment because when an NMA binds to spike protein fragments, a conformational change occurs and modifies the binding energy of ACE2 and spike protein complexes. Finally, the binding structure of ACE2 and spike protein fragments becomes unstable [ 49 , 50 ] ( Fig. 2 ).…”

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey

“…Interestingly, in silico docking and dynamics studies have recently identified ACE2 receptor as well as novel HCQ targets including the α7 nicotinic AcetylCholine Receptor (α7 nAChR), α1D-adrenergic receptor (α1D-AR), Histamine N-Methyl Transferase (HNMT) and DNA gyrase/Topoisomerase III β (Top3β) [ 64 ]. In particular, the authors found that HCQ would block virus-binding sites on both ACE2 and α7 nAChR at the entry stage, whereas at post-entry stages, HCQ would prevent viral replication by acting against Top3β, and the “cytokine storm” by inhibiting α1D-AR.…”