Non-bonding energy directed designing of HDAC2 inhibitors through molecular dynamics simulation

Designing an inhibitor having strong affinity in the active site pocket is the cherished goal of structure based drug designing. To achieve this, it is considerably important to predict which structural scaffold is better suited for change to increase affinity. We have explored five HDAC2 co-crystals having PDB ligand code-SHH (vorinostat), LLX, 20Y, IWX (BRD4884) and 6EZ (BRD7232). For analyzing protein-ligand interaction at an atomistic level, we have employed the NAMD molecular dynamics (MD) package. The obtained 100 ns long MD trajectories were subjected to quantitative estimations of non-bonding energies (NBEs) for inferring their interactions with the whole protein or its composite active site (CAS). In addition, relative ΔG_bind was calculated to rank the inhibitors. These inhibitors' NBEs reveal that the phenyl moieties are the major structural scaffold where modifications should be attempted. We designed new compounds (NCs) via introducing hydroxyl groups at 4,5 position of the phenyl moiety of 6EZ, called NC1. Improvement in NC1 further encouraged us for CAP modification by isochromane and isoindoline moieties in place of oxabicyclooctane in NC1, resulting in NC2 and NC3. We also explored trifluoromethyl oxadiazole in 6EZ (NC4 and NC5) and SHH (NC6 and NC7). This moiety acts as a ZBG in NC4 while acting as a part of the foot-pocket in the rest. NC2 and NC6 have highest favorable NBEs among all studied ligands due increased favorable electrostatic contribution. We expect these NBEs data will provide atomistic level insights and benefit in designing new and improved HDAC2 inhibitors. Communicated by Ramaswamy H. Sarma.