Vibrational Analysis of Structure Activity Relationships (SAR) in Molecular Binding

Abstract

A novel vibrational spectroscopic approach has been developed to better understand the structure activity relationship (SAR) component of the drug discovery effort. First, vibrational spectroscopy has been developed as a tool for the identification of molecular subcomponents within a compound series, which play an active role in binding kinetics. Second, vibrational spectroscopy has exhibited utility in uncovering electronic trends within both pendant functional groups and within the molecular backbone scaffold, which foster the binding process. In this study, three series of compounds (isoflavone, coumarin, and benzoxazole) within a human estrogen receptor (ER-β) study were used to explore the feasibility of the technique. In each series, infrared and Raman band shifts, which correlated with ER-β binding activity, were identified. Data indicated binding activity to be strongly influenced by electron density in the pi-bonding system of the backbone scaffold for each series. The ability to relate the physical/electronic state of a molecular subcomponent to activity has far-reaching implications in the identification and optimization of binding activity. The preliminary success of this project opens the door to a much broader investigation of the technique using a host of spectroscopic methodologies.