Submission Details

Design Rationale:

# CHEMICAL PROFILE # # Molecules designed by Benjamin P. Brown # Graduate student in the laboratory of Jens Meiler, Ph.D. # Email: benjamin.p.brown@vanderbilt.edu # # Notes on the chemical profile: # # Design protocol: Fragments co-crystalized with COVID-19 main protease (released to the PDB by von Grelft group) served as starting # scaffolds for redesign with an in-development Meiler Lab algorithm called BCL::FocusedLibraryDesign. The variation of this algorithm # utilized for this study incorporated a conventional supervised feed-forward deep neural network (DNN) as a pose-dependent protein-ligand # interface scorer. Fragments were perturbed in a Monte Carlo - Metropolis fashion using alchemical transformations, and refined at each step # to minimize clashes, optimize pose orientation, and filter out unstable/non-drug-like modifications. The best optimizations by QSAR/QSPR analysis # are recombined with BCL::LinkFragments, an in-development combinatorial chemistry algorithm. Again, molecules are optimized for clash resolution and # interaction score. The best molecules undergo a final short run of BCL::FocusedLibraryDesign, and minor manual modifications are selectively made to # intentionally increase probing of the structure-activity relationship (SAR). Finally, compounds are re-docked with RosettaLigand. The top-scoring complex # is taken to be the final pose. Note that in multiple instances there is more than 1 well-populated binding pose. Here, we simply took the best scoring # pose. We subsequently performed 3 independent molecular dynamics simulations for the best molecules. Each simulation was 1000 ns in length. Simulation details: Amber 18 ff14sb + gaff2 forcefields,TIP3P water,hydrogen mass repartitioning with 4 fs timestep, 12 angstrom water buffer, neutralizing charges.

Other Notes:

Each of these molecules was stable in a conventional MD simulation for > 1.0 microsecond in at least 3 independent trials (total of 3.0 microseconds each). Stable is defined as an RMSF (windowed at 100 ns) less than 2.0 angstroms.

Inspired By:

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