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). TSN, SHH, B3N, AGE, NHB, CRI, 5YA, 0DI and 1DI are ligands of PDBs, respectively. For these HDAC8-ligands, relative Gibbs binding free energy (ΔGbind) from MM/PBSA method and non-bonding energies (NBE) are in agreement with each other (r2=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 (NC-I to NC-VII) with encouraging energy profiles (NBE: −76.25 to −127.09 kcal/mol; ΔGbind: −17.21 to −57.42 kcal/mol) in comparison to that of the HDAC8 ligands (NBE: −46.25 to −106.29 kcal/mol; ΔGbind: −14.74 to −49.52 kcal/mol). From these, NC-VI showed best energy profile (NBE = −126.15 kcal/mol; ΔGbind = −57.42 kcal/mol) suggesting its binding affinity and thermodynamic stability. In addition to this, NC-II and NC-III have shown promising NBE and ΔGbind 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 ΔGbind profiles by modifying the unfavourable or not so favourable regions of ligands. Communicated by Ramaswamy H. Sarma

组蛋白去乙酰化酶（Histone deacetylases, HDACs）是一类锌依赖型同工酶，在细胞稳态中发挥关键作用。其中，HDAC8是极具潜力的抗癌药物靶点。为借助蛋白质-配体能量谱设计新型抑制剂，研究团队针对9组HDAC8-配体共晶体（蛋白质数据库（Protein Data Bank, PDB）编号：1T64、1T69、1T67、3F07、1W22、1VKG、5FCW、3SFF及3SFH）开展了全原子分子动力学（Molecular Dynamics, MD）模拟。其中，TSN、SHH、B3N、AGE、NHB、CRI、5YA、0DI及1DI分别对应上述PDB条目所结合的配体。针对上述HDAC8-配体体系，通过MM/PBSA方法计算得到的相对吉布斯结合自由能（ΔGbind）与非键相互作用能（NBE）具有良好的一致性（决定系数r²=0.678）。因此，研究人员利用非键相互作用能对配体的亚结构——即锌结合区、连接区与CAP结构域——进行分析。在连接区/CAP结构域中，研究鉴定出羰基、酰胺基与磺酰胺基为有利官能团，而烷基/芳基则表现出静电不利性。基于上述结论，研究人员系统性地设计了全新化合物并对其进行分子动力学模拟。结果显示，相较于原始HDAC8配体（非键相互作用能范围：-46.25 ~ -106.29 kcal/mol；相对吉布斯结合自由能范围：-14.74 ~ -49.52 kcal/mol），7个化合物（NC-I至NC-VII）展现出更优异的能量谱表现（非键相互作用能范围：-76.25 ~ -127.09 kcal/mol；相对吉布斯结合自由能范围：-17.21 ~ -57.42 kcal/mol）。其中，NC-VI的能量表现最佳（非键相互作用能：-126.15 kcal/mol；相对吉布斯结合自由能：-57.42 kcal/mol），表明其具备优异的结合亲和力与热力学稳定性。此外，NC-II与NC-III同样展现出可观的非键相互作用能与相对吉布斯结合自由能谱特征。上述化合物可作为探索HDAC8靶向癌症治疗的先导分子。本研究为通过修饰配体的不利或欠佳区域，设计具备更优非键相互作用能与相对吉布斯结合自由能谱的新型化合物提供了理论依据。本文由Ramaswamy H. Sarma通讯。