MD simulations for rational design of high-affinity HDAC4 inhibitors – Analysis of non-bonding interaction energies for building new compounds

This study investigates the contributions of non-bonding energy (NBE) to the efficacy of four HDAC4 co-crystallized inhibitors (HA3, 9F4, EBE, and TFG) through 100ns Molecular Dynamics (MD) simulations. These inhibitors contain hydroxamic acid (HA3, 9F4, EBE) or diol (TFG) as zinc-binding groups. In PDBs 2VQJ and 2VQM, the HDAC4 catalytic domain is in the 'open' conformation, while in PDBs 4CBT and 6FYZ, the same is in the 'closed' conformation. We identified HA3 as a weaker inhibitor because of the unfavorable NBE contributions from its carbonyl fragment (FR3) and hydroxamic fragment (FR1). To enhance NBE efficacy, we designed novel HA3 analogs (H01–H16) by introducing diverse fragments (–CF3, 2-hydroxyacetic acid, -NH-CH2-, 5-fluoro-2-phenyl pyrimidine, and chloroquinoline moieties). MD simulations revealed promising analogs (H02, H07, H08, H15) with strong NBEs and stable ligand-zinc retention (2.07–2.33 Å). These analogs exhibited strong relative binding free energies within their catalytic sites, highlighting their potential as novel HDAC4 inhibitors. The current study provides medicinal chemists with insights into non-covalent interactions, identifies key fragments for optimization, and offers a rational design strategy for developing more effective HDAC4 inhibitors. [Display omitted] •NBE Contributions to Inhibitor Efficacy: The study examines the role of non-bonding energy in four HDAC4 inhibitors.•Molecular Dynamics Insight: MD simulations were used to assess NBE, offering strategies for optimizing the inhibitors.•MedicinalChemistry Applications: The study highlighted non-covalent interactions in the rational design of HDAC4 inhibitors.