Molecular Design Using the Minireceptor Concept

Abstract

Explicit molecular binding pockets were constructed and optimized around sets of superimposed ligands using the minireceptor concept. The resulting binding sites incorporate the properties of the different ligands and were shown to be suitable for the design of molecules presenting novel interaction patterns. Two applications of minireceptor construction and/or optimization, followed by molecular design are described. In the pursuit of new ligands mimicking the action of paclitaxel, a minireceptor was constructed using the primary amino acid sequence of the target protein as a guide. The active site extracted from a homology-based model of the serotonin 5-HT1A receptor was optimized around a set of three ligands using the same approach.

Ligand-supported Homology Modelling of Protein Binding-sites using Knowledge-based Potentials

“…The optimisation was performed with the minireceptor modelling program Yak 38 based on an extracted active site of a homology model using three high-affinity ligands. 39 An important task in model-building proteinligand complexes is the quality assessment of the models produced, in particular if different orientations of active-site residues have to be taken into consideration. This step is usually performed by visually analysing the interaction geometry between protein and ligand functional groups.…”

A Unified and Quantitative Receptor Model for the Microtubule Binding of Paclitaxel and Epothilone

“…The second model follows from C-2 Bz/C-3‘ Ph phenyl clustering in D 2 O/[D 6 ]DMSO or CH 3 OD/D 2 O; a conformational profile is found likewise in the X-ray structure of paclitaxel . Adopting the hydrophobic solvent hypothesis (CDCl 3 ), , we used a superposition of three highly active paclitaxel analogues ((2‘ R ,3‘ S )-paclitaxel, (2‘ S ,3‘ R )-paclitaxel, and taxotere) energetically minimized in Macromodel 13 (AMBER*/H 2 O/GBSA) to construct a first-round paclitaxel−tubulin minireceptor consisting of 20 amino acids. , Both baccatin core and side chains in paclitaxel contribute to the model. The receptor residues selected 16 were taken from two patches of β-tubulin in contact with the ligand as determined by photoaffinity labeling.…”

Computational Design of New Protein Catalysts

“…The wide application of the theozyme approach has paved the way to its integral role as part of the inside-out enzyme design protocol [34]. Theozymes for nonbiological processes [44], super molecule approaches to solvation and binding [45], minireceptors for drug design quantitative structure-activity relationships (QSARs) [46], and other applications of theory to catalysis [47] have been reported, but are beyond the scope of this chapter.…”

“…Most turn out to be inactive. It has been hypothesized that once a design expresses and is soluble, any lack of activity is most likely due to rather subtle geometric deviations from the computational model, such as alternative loop and side-chain conformations in or near the active site [46]. The side chains of mutated residues would be expected to have a particularly high propensity to adopt alternative configurations, and Figure 16.7 illustrates a simplified visualization of this idea.…”