drug discovery using chemical systems biology weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir使用化学药物发现系统生物学弱抑制多个激酶可能导致奈非那韦的抗癌效果.pdfVIP

Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir 1 2 1,3 1 Li Xie , Thomas Evangelidis , Lei Xie *, Philip E. Bourne * 1 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America, 2 School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom, 3 Department of Computer Science, Hunter College, the City University of New York, New York, United States of America Abstract 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