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

Abstract

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

Keywords:

• HDAC2
• non-bonding energy
• molecular dynamics
• NAMD
• benzamide
• vorinostat

Acknowledgements

Authors thankfully acknowledge Dr. Ashish Arora, senior scientist, Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow for fruitful discussion and computational resources. CSIR-CDRI communication no. 10296.

Authors’ contribution

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

Data and software availability

The study reported in this manuscript has used Cartesian coordinates of five PDB codes reported in the PDB database as primary data. These Cartesian coordinates of PDBs are freely available at https://www.rcsb.org/. The PDBs were examined/studied in MOE2008 for the 2D interaction diagram of the ligand-binding site (active site). The ligand docking in the protein was carried out using open source software namely the AutoDock Vina plugin in UCSF Chimera. The molecular dynamics simulations were carried out using open source packages VMD1.9.3 and NAMD2. The trajectories of MD simulations were analyzed in VMD1.9.3 using appropriate scripts provided in the NAMD tutorials/manual. Relative binding free energy was determined involving the open-source CaFE plugin in VMD1.9.3. The plots were generated using the MS Excel (version 2016) and open-source software Grace (version 5.1.25). The 3D figures were generated using the UCSF chimera. Inkscape, an open-source package was used for figures processing. The animation files of trajectories were generated using the VMD1.9.3 movie plugin.

Supporting information has been provided along with the manuscript for the results and discussion. Due to the very large sizes (approx. 25GB for each simulation), the ‘.dcd files’ (trajectories) of MD simulations are not included in the supporting information. They are available from the authors upon request.

Disclosure statement

There are no conflicts to declare.

Additional information

Funding

VD and PNS thankfully acknowledge the financial support in the form of Senior Research Fellowships from Rajiv Gandhi National Fellowship, University Grants Commission, New Delhi and Department of Biotechnology, Government of India, New Delhi, respectively.