24 research outputs found
In Silico Exploration for New Antimalarials: Arylsulfonyloxy Acetimidamides as Prospective Agents
A strategy
is described to identify new antimalarial agents to
overcome the drug resistance and/or failure issues through in silico
screening of multiple biological targets. As a part of this, three
enzymes namely CTPS, CK, and GST were selected, from among 56 drug
targets of P. falciparum, and used
them in virtual screening of ZINC database entries which led to the
design and synthesis of arylsulfonyloxy acetimidamides as their consensus
inhibitors. From these, two compounds showed good activity against
sensitive (3D7; IC<sub>50</sub>, 1.10 and 1.45 μM) and resistant
(K1; IC<sub>50</sub>, 2.10 and 2.13 μM) strains of the parasite,
and they were further investigated through docking and molecular dynamics
simulations. The findings of this study collectively paved the way
for arylsulfonyloxy acetimidamides as a new class of antimalarial
agents
N-acetyl cysteine: A tool to perturb SARS-CoV-2 spike protein conformation
The infection caused by Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll
and economic consequences. The virus attaches itself to the human epithelial
cells through noncovalent bonding of its spike protein with the angiotensin-converting
enzyme-2 (ACE2) receptor on the host cell. We hypothesized that perturbing the
functionally active conformation of spike protein through reduction of its
solvent accessible disulfide bond, thereby disintegrating its structural
architecture, may be a feasible strategy to prevent infection. Proteomics data
showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely
in use in clinical medicine, forms covalent conjugates with solvent accessible
cysteine residues of spike protein that were disulfide bonded in the native
state. In silico analysis indicated that this covalent conjugation perturbed the stereo
specific orientations of the interacting key residues of spike protein that
resulted in threefold weakening in the binding affinity of spike protein with
ACE2 receptor. Antiviral assay using VeroE6 cells showed that NAC caused 54.3%
inhibition in SARS-CoV-2 replication. Interestingly, almost all SARS-Cov-2 variants conserved cystine residues
in the spike protein. Our observed results open
avenues for exploring in vivo pharmaco-preventive
and therapeutic potential of NAC for
Coronavirus Disease 2019 (COVID-19).</p