Prostate cancer (PC) is one of the leading cancers in men, raising a serious health issue worldwide. Due to lack of suitable biomarker, their inhibitors and the platform for testing those inhibitors result in poor prognosis of PC. AMP-activated protein kinase (AMPK) is a highly conserved protein kinase found in eukaryotes that is involved in growth and development, and also acts as a therapeutic target for PC. The aim of the present study is to identify novel potent inhibitors of AMPK and propose a simple cellular model system for understanding its biology. Structural modelling and MD simulations were performed to construct and refine the 3D models of Dictyostelium and human AMPK. Binding mechanisms of different drug compounds were studied by performing molecular docking, molecular dynamics and MM-PBSA methods. Two novel drugs were isolated having higher binding affinity over the known drugs and hydrophobic forces that played a key role during protein-ligand interactions. The study also explored the simple cellular model system for drug screening and understanding the biology of a therapeutic target by performing in vitro experiments.
Keywords: –; AMPK; AMPK – AMP activated protein kinase; DSSP – Dictionary of secondary structure of protein; GA – Genetic algorithm; I-TASSER – Iterative threading assembly refinement; LINCS – Linear constraint solver; MM-PBSA – Molecular mechanics Poisson–Boltzmann surface area; MMPBSA; PDB – Protein data bank; PME – Particle mesh Ewald; ProSA – Protein structure analysis; QMEAN – Qualitative model energy analysis; RIPA – Radio immune precipitation assay; RMSD – Root mean square deviation; RMSF – Root mean square fluctuation; RT-PCR; RT-PCR – Reverse transcriptase-polymerase chain reaction; Rg – Radius of gyration; SDS-PAGE – Sodium dodecyl sulphate-polyacrylamide gel electrophoresis; docking; molecular dynamics; prostate cancer.