Molecular dynamics and quantum chemistry-based approaches to identify isoform selective HDAC2 inhibitor – a novel target to prevent Alzheimer’s disease

Histone deacetylase 2 (HDAC2) is an emerging target of Alzheimer’s disease. Four featured pharmacophore model (ADRR) with one H-bond acceptor (A), one H-bond donor (D), and two aromatic rings (R) was generated using experimentally reported compounds, ((E-5[3-benzenesulfonamido) phenyl]-N-hydroxypent-2-en-4-ynamide)) and (N’-hydroxy-N-phenyloctanediamide) with IC50 values of 0.16 ± 0.11 nM and 62 ± 0.15 nM, respectively. Quantum Polarized Ligand Docking and Binding Free Energy calculation was performed for the top three identified leads RH01652, JFD02573, and HTS00800 from HitFinder database. RH01652 (methyl 2-[({5-[(benzoylamino) methyl]-2-thienyl} sulfonyl) amino]-3-(1H-indol-3-yl) propanoate) with docking score (−12.62 kcal/mol) and binding free energy (−75.27 kcal/mol), shows good binding affinity. RH01652 interacts with Gly154, His183, Glu208, and Phe210 with four H-bonds and stabilized by π–π interactions with His146, Tyr209, and Phe210. DFT studies at B3LYP level with 6-31G* basis set for the lead RH01652 reveals low band gap/ΔE (EHOMO–ELUMO) of −0.16 eV, which illustrates good reactivity of the lead. MD simulation studies (40 ns) was performed to confirm the stability of lead binding. Comparative molecular docking studies of the lead RH01652 with class I HDACs (HDAC1, HDAC2, HDAC3, and HDAC8) shows higher binding affinity towards HDAC2. Thus, lead RH01652 could serve as template to design novel and potent inhibitor of HDAC2.

组蛋白去乙酰化酶2（Histone deacetylase 2, HDAC2）是阿尔茨海默病的新兴治疗靶点。研究人员以已有实验报道的两种化合物——(E)-5-[3-(苯磺酰胺基)苯基]-N-羟基戊-2-烯-4-炔酰胺与N’-羟基-N-苯基辛二酰胺为训练集，构建了由1个氢键受体（hydrogen bond acceptor, A）、1个氢键供体（hydrogen bond donor, D）及2个芳香环（aromatic ring, R）组成的特征药效团模型（ADRR）；上述两种化合物的半最大抑制浓度（half maximal inhibitory concentration, IC50）分别为0.16 ± 0.11 nM与62 ± 0.15 nM。随后针对HitFinder数据库中筛选得到的前3个候选先导化合物RH01652、JFD02573与HTS00800，开展了量子极化配体对接（Quantum Polarized Ligand Docking）与结合自由能（Binding Free Energy）计算。其中，先导化合物RH01652的化学名称为2-[({5-[(苯甲酰胺基)甲基]-2-噻吩基}磺酰基)氨基]-3-(1H-吲哚-3-基)丙酸甲酯，其对接得分为-12.62 kcal/mol，结合自由能为-75.27 kcal/mol，展现出优异的靶点结合亲和力。该化合物可与甘氨酸154（Gly154）、组氨酸183（His183）、谷氨酸208（Glu208）及苯丙氨酸210（Phe210）形成4条氢键，并通过与组氨酸146（His146）、酪氨酸209（Tyr209）及苯丙氨酸210（Phe210）的π-π堆积相互作用实现结合稳定化。针对RH01652的密度泛函理论（Density Functional Theory, DFT）研究采用B3LYP泛函与6-31G*基组，计算结果显示其能隙ΔE（EHOMO–ELUMO）仅为-0.16 eV，表明该先导化合物具备良好的反应活性。此外，通过时长40 ns的分子动力学（Molecular Dynamics, MD）模拟实验验证了该先导化合物与靶点结合的构象稳定性。对RH01652与I类组蛋白去乙酰化酶（HDAC1、HDAC2、HDAC3及HDAC8）开展的对比分子对接研究表明，其对HDAC2具有更高的结合亲和力与选择性。综上，RH01652可作为设计新型强效HDAC2抑制剂的先导模板分子。