Investigation of HDAC8-ligands' intermolecular forces through molecular dynamics simulations: profiling of non-bonding energies to design potential compounds as new anti-cancer agents.

Histone deacetylases are zinc-dependent isoform enzymes and play important role in cellular homeostasis. Among these, HDAC8 is a potential anticancer drug target. To design new inhibitors using protein-ligand energy profiles, an all atom molecular dynamics (MD) simulations were carried out on nine HDAC8-ligand co-crystals (PDBs: 1T64, 1T69, 1T67, 3F07, 1W22, 1VKG, 5FCW, 3SFF and 3SFH). , , , , , , , and are ligands of PDBs, respectively. For these HDAC8-ligands, relative Gibbs binding free energy (Δ) from MM/PBSA method and non-bonding energies (NBE) are in agreement with each other (=0.678). Therefore, the NBEs are used to analyze ligands' sub-structures, namely zinc-binding, linker and CAP groups. For linker/CAP regions, this identified carbonyl, amide, and sulfonamide moieties as desirable and alkyl/aryl moieties as electrostatically unfavourable. Using this information, systematically new compounds were designed and subjected to MD simulations. This resulted in seven compounds () with encouraging energy profiles (NBE: -76.25 to -127.09 kcal/mol; Δ: -17.21 to -57.42 kcal/mol) in comparison to that of the HDAC8 ligands (NBE: -46.25 to -106.29 kcal/mol; Δ: -14.74 to -49.52 kcal/mol). From these, showed best energy profile (NBE = -126.15 kcal/mol; Δ = -57.42 kcal/mol) suggesting its binding affinity and thermodynamic stability. In addition to this, and have shown promising NBE and Δ profiles. These may serve as lead molecules for exploration against HDAC8 in cancer therapy. This has provided a basis for designing new compounds with improved NBE and ΔG profiles by modifying the unfavourable or not so favourable regions of ligands. [Formula: see text] Communicated by Ramaswamy H. Sarma.