Quasi-Atomistic Receptor Surface Models: A Bridge between 3-D QSAR and Receptor Modeling

Abstract

A “quasi-atomistic receptor model” refers to a three-dimensional receptor surface, populated with atomistic properties (hydrogen bonds, salt bridges, hydrophobic particles, and solvent) mapped onto it. In contrast to other 3D-QSAR approaches, an algorithm developed at our laboratory allows for the adaptation of the receptor-surface defining envelope to the topology of the individual ligand molecules. In addition, it includes H-bond flip-flop particles which can simultaneously act as H-bond donors and H-bond acceptors toward different ligand molecules, binding to the surrogate within a pharmacophore hypothesis. Such particles mimic amino- acid residues able to engage in differently directed H-bonds at the true biological receptor. Ligand−receptor interaction energies are evaluated using a directional force field for hydrogen bonds and salt bridges. On the basis of a series of ligand molecules with individually adapted receptor envelopes, the software Quasar allows a family of receptor models to be generate...