Abstract 3911: Infrared vibrational frequency as a novel molecular descriptor for lead optimization of PKB/Akt inhibitors

Abstract

Abstract We report the use of a novel molecular descriptor used for lead optimization of PKB inhibitors. Lead optimization remains a major rate limiting step in drug discovery. Current methods for lead optimization that leads to a clinical candidate often fail during clinical trials with attrition rate as high as 9 out of 10. We re-investigated the lock and key theory by incorporating the vibrational frequency of small molecules. The vibrational frequency is calculated based on the summation of all theoretical infrared vibrational frequency of each bond and normalized via division by its molecular weight. We term this molecular descriptor as MDIR. The MDIR is utilized as a rapid lead optimization computational chemistry method. The MDIR correlation to affinity/inhibition at several molecular targets shows a parabolic relationship. Quinoxalines with MDIR values near 135 provide the best inhibition (19% INH at 10 uM) at PKB/Akt as assessed via the Cisbio HTRF KinEASE assay. An internal control, 10-DEBC, known to have 100 % inhibition of PKB at 2.5 uM, had only a 6 % INH @ 10 uM in the KinEASE assay. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3911. doi:1538-7445.AM2012-3911