3D Quantitative Structure-Retention Relationship (QSRR) using comparative molecular field analysis (CoMFA) has been successfully developed for the experimental RPLC retention on a C18 column of 33 purine nucleobases for the molecular understanding of their interfacial interaction in essentially nonpolar environment as found in the inner core of phospholipid bilayer. Models based on various partial-atomic-charge formalisms resulted in robust structure-retention correlation (R2 > 0.938 and q2 > 0.693) superior to the classical QSRR in addition to the spatial information obtained as contour maps which is useful in future molecular design purposes. Further Y-randomization procedure has been performed in confirming the absence of correlation by mere chance. As long as the ab initio-optimized geometries were used, the QSRR spatial feature was rather insensitive to the particular partial charge model adopted. For readily ionizable tautomeric species at neutral pH, however, a more realistic partial charge representation was found to be critical even only for a qualitatively correct prediction. Based on the current results, CoMFA-QSRR is likely applicable to congeners of biological interests as long as the retention is governed by essentially nonpolar isotropic interactions.
Scopus Subject Areas
- Drug Discovery
- Computer Science Applications
- Organic Chemistry