I did some calculations on the covalent_warhead_db following the method described in DOI:10.3389/fchem.2018.00043
Briefly, the DB has been converted to 3D using MOE. The receptor was prepared strating from Mpro-x0830_0.pdb file. The structure was initially prepared using the “Structure Preparation->Correct” tool of MOE; the AMBER10:EHT ff and born solvation model were applied. Then, the covalent bond between Cys145 and chloroacetamide alpha carbon was broken and the system minimized by applying restraints to all heavy atoms, then by applying restraints on backbone atoms only. Then, the complex was protonated at ph=7.0 by Protonate 3D. The binding site Cys was protonated and I left it in this way.
The screening was done in a “non-covalent” manner, based on the assumption that the lowest will be the energy of the activated complex, the lowest will be the energy of the TS for covalent bonding (Hammond’s postulate)
The library was processed by requesting the enumeration of tautomers, generated by the software UNICON (only the most favoured tautomer was saved), stereoisomers and ring-conformations (generated by the software SPORES). Docking was done by PLANTS. The following “non default” parameters were added to the PLANTS input:
Binding site center=“9.50042 -1.03244 22.9953”
Binding site radius=14
chemplp_protein_hb_constraint 2210 5
The receptor, in pdb format, is attached here cov2_protease.pdb (373.6 KB) .
The top 250 compounds were then rescored with the Nwat-MMGBSA method (see reference above) with Nwat=0 (standard MMGBSA), Nwat=30 (30 explicit waters surrounding the ligand) and Nwat=60 (60 explicit waters). Point charges for the 250 rescored compounds were computed with the AM1-BCC method.
All complexes were subjected to MD (pmemd.cuda), 1.63 ns of equilibration and 1 ns of production run, as described in the paper cited above.
The final scoring three additional booleans: DIST < 5 (distance-to-warhead of Cys145); RMSD LIG < 2 ( max RMSD of ligand during MD); ST.DEV < 10% (standard deviation of Nwat-MMGBSA energies for Nwat=30). Compounds respecting these three filters were then rescored by Nwat-MMGBSA energies for Nwat=30. Rescored compounds are available here: Rescoring_with_RMSD_and_DIST2.xlsx (36.9 KB)