Novel and Rapid Method for Lead Optimization of PKB/Akt Inhibitors Utilizing Vibrational Energy of Ligands as a Molecular Descriptor

This research investigates the vibrational energy of ligands as a novel molecular descriptor. The binding of a ligand and receptor is explained by the well-known “lock and key” theory. The application of that theory in computational chemistry is often unsuccessful in drug optimization. We illustrate a ligand’s vibrational character for optimization of inhibitory potency at Protein Kinase B, an anti-cancer protein target. Our hypothesis is a ligand’s vibrational energy plays a key role in binding to target proteins. We tested this hypothesis on PKB molecules within two chemical series, quinoxolines and pyridinopyridines, based upon specific vibrational energies calculated through theoretical infrared absorptions of each molecular bond. The designed compounds were docked at PKB using MOE. The compounds with suitable docking scores were synthesized via Suzuki Coupling and Reductive Amination reactions. We purified the compounds using Biotage Isolera flash chromatography and structure elucidated using FTIR, Mass and Nuclear Magnetic Resonance spectrometers. We determined the compound’s homogeneity using TLC, LCMS and ¹H-NMR integration. We assessed a ligand’s inhibitory potency at PKB using HTRF and reported in either IC₅₀ or percent inhibition. The correlation between a ligand’s vibrational energy and PKB inhibitors is provided. Pharmaceutical drug discovery via conventional “Lock and Key” methods often provides an inaccurate model leading to excessive time in improving the drug’s potency. We provide herein a modality in the use of vibrational energy of ligands for rapid inhibitory optimization at PKB. The method offers a novel and potential solution for lead optimization in the drug discovery process.