The accurate calculation of protein/nucleic acid–ligand interactions or condensed phase properties by force field-based methods require a precise description of the energetics of intermolecular interactions. Despite the progress made in force fields, small molecule parameterization remains an open problem due to the magnitude of the chemical space; the most critical issue is the estimation of a balanced set of atomic charges with the ability to reproduce experimental properties. The LigParGen web server provides an intuitive interface for generating OPLS-AA/1.14*CM1A(-LBCC) force field parameters for organic ligands, in the formats of commonly used molecular dynamics and Monte Carlo simulation packages. This server has high value for researchers interested in studying any phenomena based on intermolecular interactions with ligands via molecular mechanics simulations. It is free and open to all at jorgensenresearch.com/ligpargen, and has no login requirements.
A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to
seek inhibitors of the main protease (M
pro
) of SARS-CoV-2, the virus
responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses
of the predicted structures of their complexes with M
pro
, 17 were chosen for
evaluation in a kinetic assay for M
pro
inhibition. Remarkably 14 of the
compounds at 100-μM concentration were found to reduce the enzymatic activity and
5 provided IC
50
values below 40 μM: manidipine (4.8 μM),
boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM),
and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern
for the binding of the active compounds to the P1, P1′, and P2 pockets of
M
pro
. Further study of the most active compounds in the context of COVID-19
therapy is warranted, while all of the active compounds may provide a foundation for
lead optimization to deliver valuable chemotherapeutics to combat the pandemic.
A quantum mechanical bespoke molecular mechanics force field is derived for the L99A mutant of T4 lysozyme and used to compute absolute binding free energies of six benzene analogs to the protein.
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