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<p>A novel coronavirus, SARS-CoV-2
has caused a recent pandemic called
COVID-19 and a severe health threat around the world. In the current situation,
the virus is rapidly spreading worldwide, and the discovery of
vaccine and potential therapeutics are critically essential. The crystal structure
for main protease (M<sup>pro</sup>) of SARS-CoV-2, 3-chymotrypsin-like
cysteine protease (3CL<sup>pro</sup>) was recently made available and is
considerably similar to previously reported SARS-CoV. Due to its essentiality
in viral replication, it represents a potential drug target. Herein,
computer-aided drug design (CADD) approach was implemented for the initial
screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>)
enzyme was accomplished and indinavir was described as a lead drug with a
docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses
an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA
compounds (>2500) was subjected to virtual screening that led to 25 hits with
a docking score more than indinavir. Exclusively, compound <b>16</b> with
docking score of -8.955 adhered to drug like parameters, and the Structure-Activity
Relationship (SAR) analysis was demonstrated to highlight the importance of
chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried
out at 100ns supported the stability of <b>16</b> within the binding pocket. Largly,
our results supported that this novel compound <b>16</b> binds to the domain I &
II, and domain II-III linker of 3CL<sup>pro</sup> protein, suggesting its
suitablity as strong candidate for therapeutic discovery against COVID-19. Lead
compound <b>16</b> could pave incredible directions for the design of novel 3CL<sup>pro</sup> inhibitors and ultimately therapeutics
against COVID-19 disease.</p>
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Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists