Computational Method for Lead Optimization of PKB/Akt Inhibitors Utilizing the Vibrational Frequency of Ligands as a Novel Molecular Descriptor

The lead optimization to discover a drug candidate in the pharmaceutical industry is time consuming and costly, often the rate-limiting step in pre-clinical, drug discovery research. This research re-evaluates the conventional lock and key theory by utilizing the vibrational frequencies of ligands as a novel molecular descriptor. The vibrational aspect of ligands is applied for lead optimization for its inhibitory potency at Protein Kinase B, a promising anti-cancer protein target. We hypothesize that the vibrational frequencies of ligands have an essential part in the binding of ligands to its protein target. Our hypothesis was tested in conjunction with molecular modeling docking studies with 9 compounds in the quinoxaline chemical series. Each compound was designed based on the sum of theoretical infrared absorptions at each molecular bond and normalized via the division by its molecular weight (MDIR). The designed compounds were then synthesized via a three-step linear synthetic approach utilizing a double condensation, palladium catalyzed hydrogenation and acid chloride coupling reactions. The structure and homogeneity of the compounds were determined via TLC, LCMS and ¹H-NMR integration. The PKB inhibitory potency of these compounds was assessed utilizing an ELISA based assay. Compounds with PKB inhibitory potency ≥ 20% at 10 μM were slated for IC₅₀ determinations. Our investigation shows one parabolic correlation of MDIR values centered at 162.4 to PKB inhibitory potency with an IC₅₀ = 4.4 μM.