Designing Plk1 Inhibitors through multiscale computational and experimental methods

通过分子模拟和分子生物学技术鉴定新型选择性Plk1抑制剂 荧光偏振实验 这项拟议研究的长期目标是确定新的非肽选择性 可用于靶向的Polo-like kinase1的Polo-box结构域(PBD)的抑制剂 癌症疗法。鉴于PLK1在有丝分裂过程中的主要作用，它是细胞增殖的标志 在某些类型的癌症中具有预后潜力。PLK1的高水平表达与 预后不佳。研究表明，PLK1表达缺失可诱导细胞凋亡 并抑制许多癌细胞的生长，而对正常细胞的影响不明显 老鼠模型。另一方面，PLK2和PLK3已被确定为肿瘤抑制因子。 因此，选择性和特异性地抑制PLK1是一种有希望的治疗策略。 癌症类型。在我们的研究中，靶向PBD而不是激酶的基本原理 催化结构域(KCD)是指KCD在激酶中是保守的，因此 选择性和毒性问题。PLK1抑制剂将通过几个步骤进行鉴定。(1)小型 已知与PLK1-3结合的分子将通过分子动力学(MD)进行研究 模拟以获得对强绑定配置文件所需的关键交互的原子洞察力 PLK1，但不是PLK2-3。(2)椰子天然产物数据库和ATOM WISE公司Small 将对分子数据库进行筛选，以确定潜在的抑制剂。最受欢迎的候选人将是 通过MD和ADMETS(吸收、分布、代谢、排泄、毒性和 稳定性)模拟，以减少候选分子的数量，最终将顶层分子 通过定向MD和荧光偏振实验进行研究。建议的研究是 在许多方面都有创新，但特别是其独特的设计，允许有意义的参与 聋哑人和重听大学生和高中生。会议的主要成果 研究表明，它有望为PBD的药物设计流水线提供起点 PLK1，并进一步指导体内实验和/或临床考虑。

Identification of Novel, Selective Plk1 Inhibitors through Molecular Modeling and Fluorescence Polarization Experiments The long-term goal of the proposed study is to identify novel nonpeptide-based selective inhibitors for polo-box domain (PBD) of polo-like kinase 1 (PLK1) that can be used for targeted cancer therapies. Given its major role in mitotic events, PLK1 is a marker for cellular proliferation with a prognostic potential in some types of cancers. A high level of PLK1 expression is associated with a poor prognosis. Studies have shown that the loss of PLK1 expression can induce apoptosis and inhibit growth in many cancer cells while showing an insignificant effect on normal cells in mouse models. On the other hand, PLK2 and PLK3 have been identified as tumor suppressors. Therefore, selective and specific inhibition of PLK1 is a promising therapeutic strategy for a range of cancer types. In our study, the rationale for targeting the PBD as opposed to the kinase catalytic domain (KCD) is that the KCD is conserved among kinases and therefore poses selectivity and toxicity problems. PLK1 inhibitors will be identified in several steps. (1) Small molecules with known binding profiles to PLK1-3 will be studied through molecular dynamics (MD) simulations to gain atomistic insights for the key interactions needed for strong binding profile for PLK1 but not for PLK2-3. (2) COCONUT natural products database and Atomwise company small molecule database will be screened to identify potential inhibitors. The top hit candidates will be studies through MD and ADMETS (absorption, distribution, metabolism, excretion, toxicity and stability) simulations to reduce the number of candidates and finally the top molecules will be studies through steered MD and fluorescence polarization experiments. The proposed study is innovative in many aspects but particularly its unique design for allowing meaningful participation of Deaf and Hard of Hearing undergraduate and high school students. Major outcome of the study is that it is expected to provide a starting point for a drug design pipeline for the PBD of PLK1 and further guide the in vivo experiments and/or clinical considerations.