基于SLEF力场和QM/MM方法的HDAC2选择性抑制剂设计研究

Zinc-dependent Histone Deacetylases (HDACs, including HDAC1-11) have emerged as attractive targets for the development of new therapeutics against cancer and various other diseases. So far a key challenge is to develop potent isoform-specific inhibitors with improved efficacy and reduced toxicity. HDAC2, which belongs to class I HDACs (including HDAC1, 3, 8), played important roles in transcriptional regulation and cell cycle progression. Recent studies also found that HDAC2 negatively regulates memory formation and synaptic plasticity. However, the crystal structure was determined very recently and the understanding of fundamental mechanisms in HDAC2 is still quite poor. Meanwhile, HDAC2 is highly homologous to other class I HDACs. So there is significant importance to probe inner mechanistic understanding in HDAC2 and it is a challenge to develop HDAC2-specific inhibitors..The final goal of this proposal is to design new mechanism-based isoform-specific HDAC2 inhibitors. The specific aims of the project are: (1) Characterize inner work mechanisms in HDAC2 by molecular dynamics simulations with our developed SLEF force field and the state-of-the-art QM(DFT)/MM methods. Then compare and illuminate the Ligand-Receptor interaction of class I HDACs(HDAC1,2,3,8). (2) Find out the key structure factor of the isoform-specifictity in HDAC2. Then to rank and computational design of structured biomimetic oligomers to specifically target HDAC2 with the Docking, MM-PBSA and Free Energy Perturbation calculation. (3) Extensive synthesis of such computational designed molecules and characterization of such potent isoform inhibitors for targeting various HDACs, to finally find the isoform-specific HDAC2 inhibitors.

组蛋白去乙酰化酶（HDACs）是当前备受瞩目的新一代靶标。目前HDACs研究的重大挑战之一是如何设计出亚型选择性抑制剂分子，以提高抑制剂的疗效并降低其毒性。HDAC2 隶属于第I类HDACs，与I 类HDACs的其它亚型（HDAC1，3，8）具有高度的同源性。它的晶体结构最近才被测定，相关的机理研究也很匮乏。因此，HDAC2选择性抑制剂的设计研究充满挑战。.本课题旨在通过基于机理的方法来设计出HDAC2选择性抑制剂：利用我们自主发展的SLEF力场，以及先进的QM(DFT)/MM方法，结合虚拟筛选、分子动力模拟、MM-PBSA和FEP等手段，在原子甚至电子水平上探讨HDAC2的内在作用机制。然后通过对I类HDACs不同亚型的比较研究，找出具有HDAC2亚型选择性的抑制剂应当具备的结构因素，进而设计出具有亚型选择性的HDAC2抑制剂分子，并最终通过生物活性实验加以验证。

组蛋白去乙酰化酶(HDACs)是目前用于治疗癌症和其他疾病的重要靶点之一，如何设计并得到具有亚型选择性的HDACs抑制剂分子，以提高抑制剂的治疗活性并降低其毒副作用是目前HDACs研究的重大挑战之一。HDAC的11个亚型中相似度(～97%)最高的就是HDAC1和HDAC2，传统的设计方法很难加以区分。本项目对HDAC2的口袋的四个组成部分Cap-Linker Binding Channel-Zinc Binding Site-Foot Pocket分别作为对象进行了详尽的分子机制研究，阐明了这四个部分对HDACs抑制剂产生选择性的潜在作用，确定了一些重要残基，随后利用HDAC1和HDAC2在第二金属位点的不同(K vs Ca)，开展SLEF力场和QM/MM水平的多尺度模拟，基于反应机制(反应性大小差异)开展了HDAC2选择性抑制剂设计，并经由实验验证，我们获得了首个也是目前唯一的具有HDAC2亚型选择性的抑制剂，即具有β-查尔酮骨架的化合物，专利已经获批。