Multi-Property Design Selective PKC_epsilon Inhibitors

描述（由申请人提供）：蛋白激酶C抑制剂已成为治疗药物的有吸引力的靶点。最近的研究表明PKC epsilon同工酶是治疗酒精中毒、炎症和酒精性多发性神经病相关的焦虑和疼痛的有效的新治疗靶点。然而，目前还没有PKC epsilon的选择性抑制剂可以系统地给药并穿过血脑屏障。近年来，我们一直在开发新的算法和计算建模、优化和虚拟筛选的技术平台，以并行选择具有平衡效价和ADMET（吸收、分布、代谢、排泄、毒性）特性的新型小分子药物先导物。我们已经在PKC同工酶的已知抑制剂的建模以及实验体外筛选方面进行了初步研究。关键的药效和结构特征及其差异，例如PKC epsilon和β 2同工酶之间的抑制已被成功鉴定。体外和体内（基于计算机的）研究的融合将使我们不仅能够更好地了解结构和药效要求，以发现新的、有效的、选择性的PKC epsilon抑制剂，而且还可以在更短的时间和更少的资源中优化和选择具有平衡ADMET特性的抑制剂。我们提出的研究项目将涉及进一步的研究，以改进和微调这些技术和体外/计算机迭代过程，并探索它们在发现新的、选择性的、口服的和脑活性的PKC epsilon抑制剂治疗酒精中毒、焦虑和疼痛方面的效用。

DESCRIPTION (provided by applicant): Protein kinase C inhibitors have been rendered as attractive targets for therapeutic agents. Recent studies have been shown that PKC epsilon isozyme is a valid new therapeutic target for treating alcoholism, anxiety and pain related to inflammation and alcoholic polyneuropathy. However, there is no selective inhibitor of PKC epsilon that can be administered systematically and cross the blood-brain barrier. Recently, we have been developing new algorithms and technology platform of computational modeling, optimization and virtual screen to parallel select novel small molecule drug leads with balanced potency and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. We have performed preliminary studies both in modeling of known inhibitors of PKC isozymes as well as in experimental in-vitro screening. The key pharmacophoric and structural features and their differences, for example, between inhibitions of PKC epsilon and beta2 isozymes have been successfully identified. The convergence of in-vitro and in-silcio (computer-based) studies will allow us to not only better understand the structural and pharmacophoric requirements for discover novel, potent, selective PKC epsilon inhibitors, but also to optimize and select them with balanced ADMET properties in a shorter time and less resources. Our proposed research project will involve further studies to improve and fine-tune these technologies and in-vitro/in-silico iterative processes and explore the utility of them in discovering new, selective, oral- and brain-active PKC epsilon inhibitors for treatment of alcoholism, anxiety and pain.