Phosphatidylinositol 3-Kinase (PI3K) Targeted Library

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase known to be a promising therapeutic target for cancer. PI3K is an important node to regulate signaling of several essential biological processes. PI3K catalyzes phosphorylation of phosphatidyl-inositide in position 3 of the inositol ring, producing important lipid second messengers. The products of PI3K activity recruit PDK1 and Akt Ser/Thr kinases to the plasma membrane where they are activated, transducing a potent proliferative and anti-apoptotic signal to the cell. Dysregulation of this signaling pathway (PI3K/PDK1/Akt (also known as protein kinase B) has been found in a variety of cancer cells. Recently, active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers [1]. Therefore, targeting PI3K is a promising approach for cancer therapy and significant efforts have been made to develop antitumor PI3K inhibitors already [2].

The structure of PI3K is well investigated and determined with numerous X-Ray structures published online in the Protein Data Bank. Thus, utilizing available structural information, we have used a receptor-based approach to design the Sharp-Focused Library of potential PI3K Inhibitors as promising anti-cancer agents.

Based on 3BV2 PDB entry [3], the Unity Query Model of protein binding site was built and validated by docking of co-crystallized ligand with RMSD value of 1.3Å (UNITY and Surflex- Dock application in SYBYL-X). The following amino acid residues were identified as important and as such they were used for the Unity Query Features preparation: Val822, Tyr 867, Asp836, Asp841, Lys833 (responsible for formation of polar contacts); Leu845, Tyr876, Ile879, Ile936 (hydrophobic interactions) (Fig.1). The Life Chemicals Stock Compounds Collection was filtered with the Rule of Five restriction and PAINS structure filters. Thereafter, the ligand dataset was prepared from the resulting compounds to go through the virtual screening. The screening procedure was launched with Flexible Search within UNITY Tool. QFit score data was used for extraction of hit compounds and preparation of the final PI3K Targeted Library.

The total number of compounds in the library is 939.

 The docking pose of a compound from the PI3K Sharp-Focused Library

Fig. 1. The binding conformation of a compound from the PI3K Sharp-Focused Library

 

References

  1. Garcia-Echeverria C., Sellers W.R. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene, 2008, 27, pp. 5511–5526.
    1. Carnero A. Novel inhibitors of the PI3K family. Expert Opin. Investig. Drugs, 2009, 18 (9), pp. 1265–1277.
  2. Ohwada J., Ebiike H. et al. Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorg. Med. Chem. Lett., 2011, 21, pp. 1767–1772.