Docking and molecular dynamics simulations studies of human protein kinase catalytic subunit alpha with antagonist

Background: Cyclic adenosine monophosphate (cAMP) dependent protein kinase A plays major role in cell signalling to undergo many cellular functions. Over expression of extracellular cAMP dependent protein kinase catalytic subunit alpha (PRKACA) causes severe tumorgenesis in prostate. Thus, computer aided high throughput virtual screening and molecular dynamics simulations studies were implemented to identify the potent leads for human PRKACA. Methods: The human PRKACA crystal structure was optimized in Maestro v9.2. Fifteen recently published PRKACA inhibitors were selected for compiling 5388 structural analogs from Ligand.Info database, these were prepared using LigPrep. Molecular docking from lesser to higher stringency towards minor steric classes was applied subsequently to the prepared ligand dataset into PRKACA active site using Glide v5.7. Molecular dynamics simulation studies were done using Desmond v3.0 to predict the activity of PRKACA-leptosidin complex. Results: Twenty lead molecules were identified. Lead-1 was observed to have relatively the least docking score compared to the identified lead molecules and 15 published inhibitors. The PRKACAleptosidin complex deciphered that leptosidin blocked the active site residues Thr-51, Glu-121, Val123, Glu-127 and Thr-183 directly through intermolecular hydrogen bonds. In molecular dynamics simulations, trajectory analysis also showed existence of water bridges between PRKACA and leptosidin. Conclusions: Docking and molecular dynamics studies revealed the better binding interaction of leptosidin with PRKACA. Leptosidin is having the better pharmacological properties thus it could be a futuristic perspective chemical compound for prostate cancer therapy.