Investigation of HDAC8-ligands’ intermolecular forces through molecular dynamics simulations: profiling of non-bonding energies to design potential compounds as new anti-cancer agents
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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). <b>TSN</b>, <b>SHH</b>, <b>B3N</b>, <b>AGE</b>, <b>NHB</b>, <b>CRI</b>, <b>5YA</b>, <b>0DI</b> and <b>1DI</b> are ligands of PDBs, respectively. For these HDAC8-ligands, relative Gibbs binding free energy (Δ<i>G</i><sub>bind</sub>) from MM/PBSA method and non-bonding energies (NBE) are in agreement with each other (<i>r</i><sup>2</sup>=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 (<b>NC-I to NC-VII</b>) with encouraging energy profiles (NBE: −76.25 to −127.09 kcal/mol; Δ<i>G</i><sub>bind</sub>: −17.21 to −57.42 kcal/mol) in comparison to that of the HDAC8 ligands (NBE: −46.25 to −106.29 kcal/mol; Δ<i>G</i><sub>bind</sub>: −14.74 to −49.52 kcal/mol). From these, <b>NC-VI</b> showed best energy profile (NBE = −126.15 kcal/mol; Δ<i>G</i><sub>bind</sub> = −57.42 kcal/mol) suggesting its binding affinity and thermodynamic stability. In addition to this, <b>NC-II</b> and <b>NC-III</b> have shown promising NBE and Δ<i>G</i><sub>bind</sub> 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<sub>bind</sub> profiles by modifying the unfavourable or not so favourable regions of ligands. Communicated by Ramaswamy H. Sarma
提供机构：
Taylor & Francis
创建时间：
2020-08-21
