Identification of a Potent Inhibitor Targeting the Spike Protein of Pandemic Human Coronavirus, SARS-CoV-2 by Computational Methods

Abstract

<p>Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein – ACE2 interface by making substantial pi-pi interactions with Tyr505 in the ‘Site 1’ hook region of RBD and hydrophilic interactions with Glu406, Ser494 and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a potent repurpose drug to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.</p>

Virtual screening FDA approved drugs against multiple targets of SARS‐CoV‐2

“…Other drugs on our short list, such as bisoxatin and selinexor are also recently identified as potent repurpose drugs to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host. 35,36 Of particular note is dexamethasone on our list, which is a corticosteroid medicine with predominantly anti-inflammatory glucocorticoid effects. The mechanism of action of dexamethasone is more on the modulation of human immune response rather than direct inhibition of viral replication.…”

“…For two drugs (capmatinib and pexidartinib) that do not meet the ADME‐Tox properties, both remain unreported for treating COVID‐19, thus deserve attention for potential repurposing against SARS‐CoV‐2. Other drugs on our short list, such as bisoxatin and selinexor are also recently identified as potent repurpose drugs to develop new chemical libraries for inhibiting SARS‐CoV‐2 entry into the host 35,36 . Of particular note is dexamethasone on our list, which is a corticosteroid medicine with predominantly anti‐inflammatory glucocorticoid effects.…”

Phyto‐pharmacological perspective of Silymarin: A potential prophylactic or therapeutic agent for COVID‐19, based on its promising immunomodulatory, anti‐coagulant and anti‐viral property

“…Furthermore, a recent in silico study suggests that silymarin may block the protein–protein interaction between viral spike glycoprotein and host cell receptor ACE2 by binding with the receptor‐binding domain (RBD) of spike protein at the RBD‐ACE2 interface to control SARS‐CoV infection (Ubani et al, 2020; Unni, Aouti, & Balasundaram, 2020). Thus, the clinical potency of silymarin could be investigated against mild, moderate, and acute infection caused by SARS‐CoV‐2, depending on the severity of the disease (Diao et al, 2020).…”

Transcriptomic analysis in renal cell carcinoma and COVID-19 patients

“…COVID-19 is caused by SARS-CoV2 (severe acute respiratory syndrome coronavirus 2), and the disease exhibits different symptoms in different people and goes from being asymptomatic to mild infection, fever, fatigue and severe critical illness (3)(4)(5). Some of the commonly found symptoms among COVID-19 patients include pneumonia, dry cough, dyspnea, sore throat, diarrhea, and in a few cases, the severe infection results in multi-organ failure, especially kidneys, ARDS (Acute Respiratory Distress Syndrome) which eventually results in death if left untreated (6). An individual's immune system and comorbidity status decide the disease's severity and prognosis.…”