Multi-Property Design Selective PKC_epsilon Inhibitors

描述（由申请人提供）：蛋白激酶C抑制剂已成为治疗剂的有吸引力的靶点。最近的研究表明，PKC β同工酶是治疗酒精中毒、焦虑、炎症相关疼痛和酒精性多发性神经病的有效新靶点。然而，没有选择性的PKC β抑制剂可以系统地施用并穿过血脑屏障。最近，我们一直在开发新的计算建模，优化和虚拟筛选的算法和技术平台，以并行选择具有平衡效力和ADMET（吸收，分布，代谢，排泄，毒性）特性的新型小分子药物先导物。我们已经进行了初步研究，在建模的PKC同工酶的抑制剂，以及在实验中的体外筛选。关键的药效学和结构特征及其差异，例如，PKC β 2同工酶抑制之间的差异已被成功确定。体外和计算机研究的融合将使我们不仅能够更好地了解发现新的，有效的，选择性PKC β抑制剂的结构和药效学要求，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特性的药物。我们提出的研究项目将涉及进一步的研究，以改善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，口服和脑活性的PKC β抑制剂治疗酒精中毒，焦虑和疼痛的效用。

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.