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

Abstract

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.

Structure‐based pharmacophore models to probe anticancer activity of inhibitors of protein kinase B‐beta (PKB β)

“…Active analog approach (Guner, ; Güner, ; Tebib, Bourguignon & Wermuth, ) was applied on already published data set of 111 quinoline derivatives (Supporting Information Table S2) (Akhtar & Jabeen, ) to select a template for pharmacophore model building. The active analog approach selects highly active and rigid chemical structure out of a large number of candidate compounds belonging to the same class for model building.…”

“…The docking solutions were further evaluated using enrichment factor (EF) metric method (Chen, Lyne, Giordanetto, Lovell & Li, ) at a given percentage (1%, 2%, 5%) of the database (111 compounds), and the results were visualized using a receiver operator characteristic (ROC) curve (Supporting Information Figure S1). However, in order to elucidate the ligand–receptor binding mode, and to obtain most probable binding conformation of the selected template, a similar docking protocol was used as explained in the previous study (Akhtar & Jabeen, ).…”

“…Briefly, the docked conformation of the selected template was uploaded in Phase (Dixon et al., ; Dixon, Smondyrev & Rao, ) module as a reference ligand. To generate pharmacophore hypotheses, the selection of pharmacophoric sites based on identified ligand – protein interactions at the active site (Akhtar & Jabeen, ) was used. The hypotheses were generated and scored using default parameters for volume, number of matches, and energy terms.…”

“…Therefore, several biological and computational attempts have also been made to design inhibitors of Akt2 with high antiproliferative potency (Fei et al., ; Hartnett et al., ; Vyas, Ghate & Goel, ). Till date, most of the known inhibitors against PH domain of Akt2 possess quinoline common scaffolds (Akhtar & Jabeen, ; Lindsley et al., ; Wu et al., ; Zhao et al., , ). Therefore, it is important to identify new arsenal of potentially selective inhibitors of Akt2.…”

“…The performance of the final pharmacophore model was evaluated by Matthews correlation coefficient (MCC) (Baldi, Brunak, Chauvin, Andersen & Nielsen, ; Matthews, ) true positive and true negative rate. Additionally, IC 50 values of selected hits from a chemical structure database provided by ChemBridge Corp () against Akt2 have been predicted by our in‐house GRIND (Grid‐independent molecular descriptor) model (Akhtar & Jabeen, ). The predicted activity values (IC 50 ) of the retrieved 14 potential hit compounds range from 0.50 to 0.62 μM which are comparable to the biological activities of already known potent quinoline‐type inhibitors against PH domain of Akt2.…”