PARP1作为新机制的抗肿瘤药物靶标，基于“合成致死”策略，其抑制剂可选择性阻断BRCA缺陷性肿瘤的DNA损伤修复，是潜在的高效低毒的肿瘤靶向性抗肿瘤药物。依据本课题前期获得的选择性PARP1抑制剂先导结构，采用结构生物学方法和分子模拟技术，利用PARP1和PARP2结合腔中关键差异性氨基酸残基，设计合成喹唑啉二酮和咪唑并哌嗪酮类选择性抑制剂。经酶学、细胞和体内活性评价，获得高活性和高选择性PARP1抑制剂。本课题的另一研究重点是将热力学和动力学用于选择性抑制剂研究，测定代表性化合物与PARP1结合过程中的热力学参数(ΔG，ΔH和ΔS)和动力学参数（kon, koff, τ），结合分子模拟，在深层次上挖掘分子设计内涵，指导分子设计和侯选药物选择。

Poly(ADP-ribose) polymerase-1 (PARP1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. Due to its “synthetic lethality" mechanism with BRCA , PARP1 inhibitors are expected to be highly potent and less toxic anticancer agents. In this project, based on the lead structure of selective PARP1 inhibitor discovered in our previous work and the distinct key amino acids in the binding pocket of PARP1 and PARP2, novel compounds with quinazoline-dione or imidazole-piperidinone scaffold were designed by using structure biology method and molecular modeling technique. The inhibitory activities will be evaluated both in vitro and in vivo so as to discover novel highly potent and selective PARP1 inhibitors as anticancer drug candidate. Furthermore, the thermodynamic and kinetic parameters of the potent and selective PARP1 inhibitors will be measured in order to disclose the distinct thermodynamic and kinetic features of various inhibitors. In combination with molecular modeling and computational chemistry, the binding nature in microscopic level of selective PARP1 inhibitors will be explored and used to guide the molecular design and drug candidate selection.