ABSTRACT
SARS-CoV-2, a new coronavirus emerged in 2019, causing a global healthcare epidemic. Although a variety of drug targets have been identified as potential antiviral therapies, and effective candidate against SARS-CoV-2 remains elusive. One of the most promising targets for combating COVID-19 is SARS-CoV-2 Main protease (Mpro, a protein responsible for viral replication. In this work, an in-house curated library was thoroughly evaluated for druggability against Mpro. We identified four ligands (FG, Q5, P5, and PJ4) as potential inhibitors based on docking scores, predicted binding energies (MMGBSA), in silico ADME, and RMSD trajectory analysis. Among the selected ligands, FG, a natural product from Andrographis nallamalayana, exhibited the highest binding energy of -10.31 kcal/mol close to the docking score of clinical candidates Boceprevir and GC376. Other ligands (P5, natural product from cardiospermum halicacabum and two synthetic molecules Q5 and PJ4) have shown comparable docking scores ranging -7.65 kcal/mol to -7.18 kcal/mol. Interestingly, we found all four top ligands had Pi bond interaction with the main amino acid residues HIS41 and CYS145 (catalytic dyad), H-bonding interactions with GLU166, ARG188, and GLN189, and hydrophobic interactions with MET49 and MET165 in the binding site of Mpro. According to the ADME analysis, Q5 and P5 are within the acceptable range of drug likeliness, compared to FG and PJ4. The interaction stability of the lead molecules with viral protease was verified using replicated MD simulations. Thus, the present study opens up the opportunity of developing drug candidates targeting SARS-CoV-2 main protease (Mpro) to mitigate the disease.
ABSTRACT
Coronavirus disease (COVID-19), declared as a pandemic has affected millions of people and caused unprecedented number of death. The disease is caused by a severe acute respiratory syndrome related coronaviruses-2 virus which enters cells by binding with the host angiotensin converting enzyme-2 and CD147 protein. Among COVID-19 patients admitted to a hospital, hypertension, diabetes and obesity are the most common co-morbidities. A majority of COVID-19 hospitalized patients are found to have proteinuria and hematuria which is associated with higher risk of in-hospital mortality. Studies have reported high incidence of acute kidney injury (AKI) among COVID-19 patients admitted to hospital (10 to 43%) and intensive care unit (43-75%). These patients with AKI have much higher need for mechanical ventilation, vasopressor use and critical care. In addition, proportion of patients with AKI who require renal replacement (RRT) therapy is greatly increased. Acute tubular injury, cytokine storm induced systemic inflammatory response, endothelial injury and dysfunction are the main mechanisms of AKI. In addition, direct viral invasion of tubules, lymphocytic infiltration and complement mediated (C5b- 9) related injury is also seen. Mortality risk among patients with AKI and those in need of RRT is greatly amplified. Appropriate timing and choice of RRT for these patients is not well defined but will need to take in account the clinical condition, anticipation of their clinical course and availability of dialysis resources. Risk of AKI and death is also increased among kidney recipients and patients with chronic kidney disease.
ABSTRACT
Coronavirus disease has caused seven million infections worldwide, of which, 3.1 million individuals have recovered. Though, most individuals develop antibodies, whether these antibodies result in clinical improvement/immunity from future infection is not known. It is also not known about durability of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). No human re-infection with SARS-CoV-2 has been confirmed to date, although a few case reports have mentioned patients who have tested positive again after recovery from the initial illness. Whether these cases represent a state of carrier or re-infection or reactivation, is not known. Nevertheless, the possibility of re-infection remains a matter of concern and yet another question about SARS-CoV-2 which is still unanswered.