In the pharmaceutical industry, drug discoveryis a very costly and time consuming process. This is particularly true during the lead optimization process which isgenerally the rate-limiting step in drug discovery research.  We hypothesize that using vibrationalfrequencies of the ligand is an important and novel molecular descriptor forbinding interactions with target proteins. By incorporating this concept into the lock and key method, we should beable to decrease the amount of time and money spent in lead optimization.  We applied this method to four differentchemical series: pyridinopyrazines, quinoxalines, quinoxaline N-amides, and amides.  This method was utilized in an attempt to targeta promising yet elusive oncology protein, Protein Kinase B (PKB).  Compounds were designed based on the sum oftheir theoretical infrared absorptions at each molecular bond and normalizedvia division by its molecular weight (MDIR). Fifty-four compounds were then synthesized via Suzuki coupling,reductive amination, acetylation, or amide formation.  Assessment of purity was then done using TLC,LCMS and 1H-NMR.  Afterdetermining purity, we conducted ELISA based assays to determine percent inhibitionof each molecule for PKB.  The IC50was then evaluated for any molecules with inhibition >20% at 10�M.  Correlation between the MDIR or FTIR valuesand IC50s were then evaluated for lead optimization.  A positive parabolic relation between MDIRand PKB inhibitors was observed in quinoxaline analogs with an IC50 range of1.8 � 11.3 �M.  The use of MDIR providesa novel modality for lead optimization in drug discovery.

Utility of infrared vibrational frequencies for the lead optimization of quinoxalines, and pyridinopyrazines as PKB/akt inhibitors

245th National Meeting (2013)

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