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12th November 2017 @ 00:18

My docking experiments of OSM-S-106 vs all crystal structures of Plasmodium kinases supports PKA (protein kinase A) as the top target (PDB 5kbf).

OSM-S-106 was docked into the ligand binding site with the target side chains free to rotate as described in the previous entry. The docked structure was then energy minimized in Yasara with the Yasara2 force field with explicit water molecules in a 6A dodecahedral box. Three cycles of simulated annealing energy minimization were performed. The energy minimized coordinates are attached. Visual inspection showed that OSM-S-106 was bound quite tightly in its pocket, especially the sulfonamide end, leaving little room for chemical extension. This would be consistent with the SAR data.

All the compounds in Series 3 were then aligned to the cAMP site using a combined ligand-based and force-field based method in Cresset Forge, with protein structure (pdb 5kbf) set as medium strength restraints. I then created a number of modifications of OSM-S-106 that I considered compatible with the binding mode. OSM-S-106 had a Cresset Forge Sim score of 0.606. The following compounds had similar or better Sim scores.

OSM-S-106-5   Sim=0.637
OSM-S-106-3   Sim=0.608
OSM-S-106-4   Sim=0.600
OSM-S-106-6   Sim=0.570

I do not place much weight in these scores. Rather, I interpret them as meaning that these compounds are worth exploring experimentally. Compounds are attached as MarvinSketch (Chemaxon) files.

Attached Files
11th November 2017 @ 23:14

I focused on OSM-S-106, the most active of the Series 3 compounds. I docked OSM-S-106 vs all Plasmodium falciparum kinase crystal structures in the PDB, using smina, the Vinardo scoring function, and flexible side chains.

PDB Name Score
4qox CDPK4 -10.3
4mvf CDPK2 -8.7
3ltt CLK1 -11.8
5kbf PKA-R -13.0
2yog thymidylate kinase -11.4
2bsx purine nucleoside phosphorylase -9.4
1v0p PfPK5 -11.4
5lm3 nicotinic acid mononucleotide adenylyltransferase cannot dock
5tpx Bromodomain Gcn5 -9.7
5llt NMNAT1 cannot dock
3q5i CDPK1 -10.0

More negative scores are better. Top scores go to 5kbf (PKA-R), 3ltt (CLK1), 2yog (thymidylate kinase), 1v0p (PfPK5), with 5kbf considerably better than the others.

Docked complexes are attached below as zipped pdb files.

Attached Files