| Title |
Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir
|
|---|---|
| Published in |
PLoS Computational Biology, April 2011
|
| DOI | 10.1371/journal.pcbi.1002037 |
| Pubmed ID | |
| Authors |
Li Xie, Thomas Evangelidis, Lei Xie, Philip E. Bourne |
| 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 targeted polypharmacology agent. |
X Demographics
The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Japan | 1 | 50% |
| Canada | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 50% |
| Scientists | 1 | 50% |
Mendeley readers
The data shown below were compiled from readership statistics for 209 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 12 | 6% |
| United Kingdom | 4 | 2% |
| Spain | 3 | 1% |
| Italy | 1 | <1% |
| Israel | 1 | <1% |
| France | 1 | <1% |
| Canada | 1 | <1% |
| China | 1 | <1% |
| Colombia | 1 | <1% |
| Other | 4 | 2% |
| Unknown | 180 | 86% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 66 | 32% |
| Student > Ph. D. Student | 40 | 19% |
| Student > Master | 19 | 9% |
| Student > Bachelor | 12 | 6% |
| Professor > Associate Professor | 11 | 5% |
| Other | 43 | 21% |
| Unknown | 18 | 9% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 71 | 34% |
| Chemistry | 29 | 14% |
| Biochemistry, Genetics and Molecular Biology | 23 | 11% |
| Computer Science | 18 | 9% |
| Medicine and Dentistry | 10 | 5% |
| Other | 31 | 15% |
| Unknown | 27 | 13% |