Files attached. Original post on GHI526. Licence, as for all OSM content, CC-BY.
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.
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.
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.
Malaria is a majority of dangerous disease in some poor area, which will kill a lot of people. Also, there are most of drug which has drug resistance. Hence, Open Source Malaria was created in that moment. This experiment is included in the project of Open Source Malaria. This experiment uses 2,6-dichloropyrazine as the start material. During the whole produces, the experiment used the Thin layer chromatography(TLC), which uses molecular polar to separate mixture and check the reaction to be reacted and Nuclear Magnetic Resonance spectroscopy (NMR), which can identify the different chemical environmental hydro to make sure about the purify product. Both of them are useful technologies, to analysis and check whether the each step’s product is purification. Otherwise, there is some errors in experiment. Finally, the experiment could not do the last step to synthesis the target because some compound or some chemical environment which can not allow the reaction to be done. The experiment is unsuccessful.
Masses and measurements:
Hydrazone - 1.5054g, 4.84mmol
BAIB - 1.7038g, 5.29mmol
Dichloromethane - 30mL
The hydrazone product (1.5054g, 4.84mmol) was dissolved in a RBF using dichloromethane (30mL) whilst being stirred. Once the solid was fully dissolved, BAIB (1.7038g, 5.29mmol) was added to the reaction mixture and the mixture was left to stir for 2-3 hours. The reaction mixture was a thick cloudy orange mixture and continued to look the same until the end of the reaction. Next the reaction was quenched by adding NaHCO3 (30mL) and the remaining solution was extracted and seperated using ethyl acetate (3x40mL). Next the retained organic layers were dried with MgSO4 and the precipitate was filtered out leaving behind the filtrate of organic layers which was subsequently rotary evaporated leaving behind an orange solid. The remaining solid was then seperated on a flash column (1:1 ethyl acetate & pet ether) where it was found that test tubes 1-17 contained the end product; these test tubes were combined, rotary evaporated and the product of 3-(4-bromophenyl)-5-chloro-[1,2,4]triazolo[4,3,a]pyrazine (0.5854g, 39.13%) was formed as a pale orange crystal like solid.
Step 1 online lab book.jpg
4-bromobenzaldehyde - 2.0559g, 11.1mmol
2-chloro-6-hydrazinylpyrazine - 1.6399g, 11.3mmol
Ethanol - 25mL
4-bromobenzaldehyde (2.0559g, 11.1mmol) was dissolved in ethanol (25mL) and stirred in a RBF. Once the solid was dissolved in the ethanol, the 2-chloro-6-hydrazinylpyrazine (1.6399g, 11.3mmol) was slowly added to the stirring reaction mixture. The solution was colourless until the pyrazine was added, which was when the reaction mixture turned an orange foamy mixture. The mixture was stirred for a few hours until TLC analysis (70% pet ether & 30% ethyl acetate) suggested the reaction was complete. The resulting reaction mixture was filtered under vacuo, washed with ethanol and dried over air. The remaining solid product of (E)-2-(2-(4-bromobenzylidene)-6-chloropyrazine (3.2011g, 92.62%) was obtained as an orange powdery solid.