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. 2012 Feb 15;22(4):1629-32.
doi: 10.1016/j.bmcl.2011.12.121. Epub 2012 Jan 4.

New inhibitor of 3-phosphoinositide dependent protein kinase-1 identified from virtual screening

Wenchao Yang  1 , Mohamed Diwan M AbdulHameed, Adel Hamza, Chang-Guo Zhan
Affiliations

New inhibitor of 3-phosphoinositide dependent protein kinase-1 identified from virtual screening

Wenchao Yang et al. Bioorg Med Chem Lett. .

Abstract

3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been recognized as a promising anticancer target. Thus, it is interesting to identify new inhibitors of PDK1 for anticancer drug discovery. Through a combined use of virtual screening and wet experimental activity assays, we have identified a new PDK1 inhibitor with IC(50)=~200 nM. The anticancer activities of this compound have been confirmed by the anticancer activity assays using 60 cancer cell lines. The obtained new PDK1 inhibitor and its PDK1-inhibitor binding mode should be valuable in future de novo design of novel, more potent and selective PDK1 inhibitors for future development of anticancer therapeutics.

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Figures

Figure 1
Figure 1
Flowchart of the combined virtual screening and experimental activity assays used.
Figure 2
Figure 2
(A) Molecular structures of the new PDK1 inhibitor (compound 1) identified through virtual screening and the corresponding scaffold (2); (B) in vitro inhibitory activity of compound 1 against PDK1.
Figure 3
Figure 3
Growth inhibitory effect of compound 1 against representative cancer cell lines
Figure 4
Figure 4
Binding of compound 1 in the PDK1 active site. Compound 1 is shown in sticks with carbon atoms in green color.
Figure 5
Figure 5
Plots of MD-simulated internuclear distances versus simulation time for PDK1 binding with compound 1. D1 refers to the distance between N1 atom of compound 1 and the carbonyl oxygen of Ala162 backbone, D2 the distance between N3 atom of compound 1 and the carbonyl oxygen of Leu88 backbone, and D3 the distance between N4 atom of compound 1 and the carbonyl oxygen of Leu88 backbone.
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