Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America.
PLoS Comput Biol. 2011 Apr;7(4):e1002037. doi: 10.1371/journal.pcbi.1002037. Epub 2011 Apr 28.
Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent.
奈非那韦是一种强效的 HIV 蛋白酶抑制剂，对癌细胞具有多种作用。实验研究将其抗癌作用与 Akt 信号通路的抑制联系起来，但实际的分子靶点仍不清楚。本研究使用结构蛋白质组学的药物脱靶谱分析方法，该方法将分子动力学模拟和 MM/GBSA 自由能计算与配体结合位点比较和生物网络分析相结合，我们鉴定了奈非那韦的潜在人类脱靶靶点，并分析了对相关生物过程的影响。我们的结果表明，奈非那韦能够抑制蛋白激酶超家族的多个成员，这些成员参与调节与致癌和转移有关的细胞过程。计算预测得到了激酶活性测定的支持，与现有实验和临床证据一致。这一发现为解释奈非那韦广谱抗癌作用提供了分子基础，并为将该药物作为一种靶向多药理学药物进行优化提供了机会。
