Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain

• Published in: Bioorganic & medicinal chemistry 2009-10, Vol.17 (19), p.6983-6992
• Main Authors: Du-Cuny, Lei, Song, Zuohe, Moses, Sylvestor, Powis, Garth, Mash, Eugene A., Meuillet, Emmanuelle J., Zhang, Shuxing
• Format: Article
• Language: English
• Subjects: Akt inhibitors; Anticancer drugs; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Blood Proteins - chemistry; Caco-2 Cells; Cell Membrane Permeability; Cell permeability; Computer Simulation; Drug Discovery; Drug Screening Assays, Antitumor; Humans; In silico drug design; Metabolism; Models, Molecular; Molecular docking/scoring; Phosphoproteins - chemistry; Pleckstrin homology domain; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - chemistry; QSAR; Quantitative Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.08.022

Computational modeling continues to play an important role in novel therapeutics discovery and development. In this study, we have investigated the use of in silico approaches to develop inhibitors of the pleckstrin homology (PH) domain of AKT (protein kinase B). Various docking/scoring schemes have been evaluated, and the best combination was selected to study the system. Using this strategy, two hits were identified and their binding behaviors were investigated. Robust and predictive QSAR models were built using the k nearest neighbor ( kNN) method to study their cellular permeability. Based on our in silico results, long flexible aliphatic tails were proposed to improve the Caco-2 penetration without affecting the binding mode. The modifications enhanced the AKT inhibitory activity of the compounds in cell-based assays, and increased their activity as in vivo antitumor testing.