Computer simulated screening of dentin bonding primer monomers through analysis of their chemical functions and their spatial 3D alignment.

Binding interactions between dentin bonding primer monomers and dentinal collagen were studied by an analysis of their chemical functions and their spatial 3D alignment. A trial set of 12 monomers used as primers in dentin adhesives was characterized to assess them for binding to a complementary target. HipHop utility in the Catalyst software from Accelrys was used for the study. Ten hypotheses were generated by HipHop procedures involving (a) conformational generation using a poling technique to promote conformational variation, (b) extraction of functions to remodel ligands as function-based structures, and (c) identification of common patterns of functional alignment displayed by low energy conformations. The hypotheses, designated as pharmacaphores, were also scored and ranked. Analysis of pharmacaphore models through mapping of ligands revealed important differences between ligands. Top-ranked poses from direct docking simulations using type 1 collagen target were mapped in a rigid manner to the highest ranked pharmacophore model. The visual match observed in mapping and associated fit values suggest a strong correspondence between direct and indirect docking simulations. The results elegantly demonstrate that an indirect approach used to identify pharmacaphore models from adhesive ligands without a target may be a simple and viable approach to assess their intermolecular interactions with an intended target. Inexpensive indirect/direct virtual screening of hydrophilic monomer candidates may be a practical way to assess their initial promise for dentin primer use well before additional experimental evaluation of their priming/bonding efficacy. This is also of value in the search/design of new compounds for priming dentin. Copyright 2008 Wiley Periodicals, Inc.