Open AccessLigand-based pharmacophore modeling; atom-based 3D-QSAR analysis and molecular docking studies of phosphoinositide-dependent kinase-1 inhibitors
Author(s) -
Palani Kirubakaran,
Karthikeyan Muthusamy,
Kamya Singh,
Selvaraman Nagamani
Publication year - 2012
Publication title -
indian journal of pharmaceutical sciences/indian journal of pharmaceutical sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.245
H-Index - 57
eISSN - 1998-3743
pISSN - 0250-474X
DOI - 10.4103/0250-474x.103846
Subject(s) - pharmacophore , quantitative structure–activity relationship , hydrogen bond , docking (animal) , chemistry , ligand (biochemistry) , phosphoinositide 3 kinase , stereochemistry , computational biology , kinase , molecular model , biochemistry , biology , signal transduction , pi3k/akt/mtor pathway , receptor , medicine , molecule , nursing , organic chemistry
Phosphoinositide-dependent kinase-1 plays a vital role in the PI3-kinase signaling pathway that regulates gene expression, cell cycle growth and proliferation. The common human cancers include lung, breast, blood and prostate possess over stimulation of the phosphoinositide-dependent kinase-1 signaling and making phosphoinositide-dependent kinase-1 an interesting therapeutic target in oncology. A ligand-based pharmacophore and atom-based 3D-QSAR studies were carried out on a set of 82 inhibitors of PDK1. A six point pharmacophore with two hydrogen bond acceptors (A), three hydrogen bond donors (D) and one hydrophobic group (H) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least square statistics results. The training set correlation is characterized by partial least square factors (R(2) = 0.9557, SD = 0.2334, F = 215.5, P = 1.407e-32). The test set correlation is characterized by partial least square factors (Q(2) ext = 0.7510, RMSE = 0.5225, Pearson-R =0.8676). The external validation indicated that our QSAR model possess high predictive power with good value of 0.99 and value of 0.88. The docking results show the binding orientations of these inhibitors at active site amino acid residues (Ala162, Thr222, Glu209 and Glu166) of phosphoinositide-dependent kinase-1 protein. The binding free energy interactions of protein-ligand complex have been calculated, which plays an important role in molecular recognition and drug design approach.