A 2D-QSAR and Grid-Independent Molecular Descriptor (GRIND) Analysis of Quinoline-Type Inhibitors of Akt2: Exploration of the Binding Mode in the Pleckstrin Homology (PH) Domain

• Published in: PloS one Vol. 11; no. 12; p. e0168806
• Main Authors: Akhtar, Noreen, Jabeen, Ishrat
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-12-2016; Public Library of Science (PLoS)
• Subjects: AKT protein; AKT2 protein; Amino acids; Amino Acids - metabolism; Anchors; Antagonists; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; Binding; Binding Sites; Biology and Life Sciences; Breast carcinoma; Cancer; Cell growth; Cell proliferation; Chemistry; Chemotherapy; Datasets; Docking; Drugs; Growth factors; Homology; Humans; Hydrogen; Hydrogen Bonding; Hydrogen bonds; Hydrogen ion concentration; Hydrophobicity; Inhibition; Inhibitors; Isoforms; Kinases; Ligands; Medical prognosis; Medicine and Health Sciences; Methods; Musculoskeletal system; Neoplasms - drug therapy; Neoplasms - metabolism; Ovarian carcinoma; Pancreas; Pharmaceutical sciences; Pharmacology; Phosphorylation; Physical Sciences; Pleckstrin; Pleckstrin Homology Domains - physiology; Protein Isoforms - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Quantitative Structure-Activity Relationship; Quinoline; Quinolines - pharmacology; Regulators; Research and Analysis Methods; Side effects; Structure-activity relationships; Studies; Threonine; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0168806

Protein kinase B-β (PKBβ/Akt2) is a serine/threonine-specific protein kinase that has emerged as one of the most important regulators of cell growth, differentiation, and division. Upregulation of Akt2 in various human carcinomas, including ovarian, breast, and pancreatic, is a well-known tumorigenesis phenomenon. Early on, the concept of the simultaneous administration of anticancer drugs with inhibitors of Akt2 was advocated to overcome cell proliferation in the chemotherapeutic treatment of cancer. However, clinical studies have not lived up to the high expectations, and several phase II and phase III clinical studies have been terminated prematurely because of severe side effects related to the non-selective isomeric inhibition of Akt2. The notion that the sequence identity of pleckstrin homology (PH) domains within Akt-isoforms is less than 30% might indicate the possibility of the development of selective antagonists against the Akt2 PH domain. Therefore, in this study, various in silico tools were utilized to explore the hypothesis that quinoline-type inhibitors bind in the Akt2 PH domain. A Grid-Independent Molecular Descriptor (GRIND) analysis indicated that two hydrogen bond acceptors, two hydrogen bond donors and one hydrophobic feature at a certain distance from each other were important for the selective inhibition of Akt2. Our docking results delineated the importance of Lys30 as an anchor point for mapping the distances of important amino acid residues in the binding pocket, including Lys14, Glu17, Arg25, Asn53, Asn54 and Arg86. The binding regions identified complement the GRIND-based pharmacophoric features.