Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, University of Pittsburgh, 3501 Terrace Street, PA, United States.
School of Pharmacy, University of Pittsburgh, 335 Sutherland Drive, 206 Salk Pavilion, PA, United States.
Curr Cancer Drug Targets. 2019;19(9):716-728. doi: 10.2174/1568009619666190206122149.
Autophagy and apoptosis are the basic physiological processes in cells that clean up aged and mutant cellular components or even the entire cells. Both autophagy and apoptosis are disrupted in most major diseases such as cancer and neurological disorders. Recently, increasing attention has been paid to understand the crosstalk between autophagy and apoptosis due to their tightly synergetic or opposite functions in several pathological processes.
This study aims to assist autophagy and apoptosis-related drug research, clarify the intense and complicated connections between two processes, and provide a guide for novel drug development.
We established two chemical-genomic databases which are specifically designed for autophagy and apoptosis, including autophagy- and apoptosis-related proteins, pathways and compounds. We then performed network analysis on the apoptosis- and autophagy-related proteins and investigated the full protein-protein interaction (PPI) network of these two closely connected processes for the first time.
The overlapping targets we discovered show a more intense connection with each other than other targets in the full network, indicating a better efficacy potential for drug modulation. We also found that Death-associated protein kinase 1 (DAPK1) is a critical point linking autophagy- and apoptosis-related pathways beyond the overlapping part, and this finding may reveal some delicate signaling mechanism of the process. Finally, we demonstrated how to utilize our integrated computational chemogenomics tools on in silico target identification for small molecules capable of modulating autophagy- and apoptosis-related pathways.
The knowledge-bases for apoptosis and autophagy and the integrated tools will accelerate our work in autophagy and apoptosis-related research and can be useful sources for information searching, target prediction, and new chemical discovery.
自噬和细胞凋亡是细胞内清除衰老和突变细胞成分甚至整个细胞的基本生理过程。自噬和细胞凋亡在大多数重大疾病中都被破坏，如癌症和神经紊乱。最近，由于自噬和细胞凋亡在几种病理过程中具有紧密协同或相反的功能，人们越来越关注理解它们之间的串扰。
本研究旨在协助自噬和细胞凋亡相关药物研究，阐明这两个过程之间的强烈而复杂的联系，并为新药物的开发提供指导。
我们建立了两个专门针对自噬和细胞凋亡的化学基因组数据库，包括自噬和细胞凋亡相关的蛋白质、途径和化合物。然后，我们对细胞凋亡和自噬相关蛋白进行了网络分析，并首次研究了这两个紧密相连的过程的全蛋白质-蛋白质相互作用（PPI）网络。
我们发现的重叠靶标彼此之间的联系比全网络中的其他靶标更紧密，这表明药物调节的疗效潜力更好。我们还发现，凋亡和自噬相关途径中的关键连接点是死亡相关蛋白激酶 1（DAPK1），这一发现可能揭示了该过程中一些微妙的信号机制。最后，我们展示了如何利用我们的综合计算化学基因组学工具，对能够调节自噬和细胞凋亡相关途径的小分子进行虚拟靶标识别。
凋亡和自噬的知识库以及集成工具将加速我们在自噬和细胞凋亡相关研究中的工作，并可作为信息搜索、靶标预测和新化学发现的有用资源。
