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 aminoacid 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 generated using a genetic algorithm combined with cross-validation. Our concept has been used to derive semiquantitative structure-activity relationships for the β2-adrenergic, aryl hydrocarbon, cannabinoid, neurokinin-1, and sweet-taste receptor as well as for the enzyme carbonic anhydrase. The receptor surrogates for these systems are able to predict free energies of ligand binding for independent sets of test ligand molecules within 0.4-0.8 kcal/mol (RMS) of the experimental value.

Combining structure-based drug design and pharmacophores

“…1 The pocket structures were saved in pdb format suitable for the generation of structure based queries. Only studies with the 'weighted' pocket are presented below, as it allows an indirect comparison with the techniques and results of our ligand-based pharmacophore [16].…”

“…Other such combinations of computational tools have been utilised by different groups to augment the capabilities of the individual tools: 3D QSAR and receptor modelling [1], pharmacophores and molecular docking [2,3], pharmacophores and receptor modelling [2,4], pharmacophores and pseudoreceptor modelling [5,6] and pharmacophores and 3D QSAR with excluded volumes from crystallographic protein structures [7,8], as well as structure-based pharmacophores from crystal structures [9,10]. Some groups have developed in house software [11,12], e.g.…”

5D-QSAR for spirocyclic σ1 receptor ligands by Quasar receptor surface modeling

“…The quasi-atomistic receptor modeling software Quasar 5.0 is a useful tool to create pseudoreceptor models, which can be treated as binding site surrogates [39,40]. The generation of the pseudoreceptor model is based on a 6D-QSAR technique, taking the 3D structure of the ligands, ensembles of e.g.…”

Induced Fit—The Key for Understanding LSD Activity? A 4D-QSAR Study on the 5-HT2A Receptor System

“…0.0) upon receptor binding [38] E solv.,lig : Ligand desolvation energy [37] DE int.,lig : Change in ligand internal energy (DE ! 0.0) upon receptor binding [31] E env.adapt.,lig : Energy uptake (E ! 0.0) required for modifying the receptor enevelope [25±27]…”