Molecular modeling in drug design: A case study on discovery of new PDK1 inhibitors as anticarcinogenic agents

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a member of serine/threonine kinase family which plays an important role in signaling pathways activated by several growth factors and hormones. Recent data have revealed that the alteration of PDK1 is a critical component of oncogenic phosphoinositide 3-kinase signaling in breast cancer, suggesting that inhibition of PDK1 can inhibit breast cancer progression. Thus, targeting PDK1 may be a valuable anticancer strategy that may improve the efficacy of chemotherapeutic strategies in breast cancer patients. In this study, pharmacophore model was generated by using previously reported 2-aminopyrimidine based PDK1 inhibitors. The best pharmacophore model generated consisted of five features ADDRR: one hydrogen bond acceptor (A), two hydrogen bond donors (D) and two aromatic rings (R). Based on derived pharmacophore, an atom based 3D-QSAR model having r2=0.944 and q2 = 0.718 was developed to evaluate the structure activity relationships. Docking study was performed which validated pharmacophore and 3D-QSAR models. Two potent hits were identified by screening in-house natural product database by structure based virtual screening approach. In silico toxicity prediction study was performed to evaluate safety of the retrieved hits.