Docking concepts

Scheme 9.9 Biohydroxylation utilizing the docking/protecting group concept.

CPU time. In response to these slow and rigorous calculations, many fast heuristic approaches have been developed that are based on intuitive concepts such as docking [10], matching pharmacophores [19], or linear free energy relationships [20], A disadvantage of many simple heuristic approaches is their susceptibility to generalization error [17], where accuracy of the predictions is limited to the training data. 

Recently, the synthesis of (5)-2-hydroxy-2-methylbutyric acid has been reported using the docking/protecting group concept and HNL from Hevea brasiliensis (ffl>HNL) as catalyst (Scheme 8.1). ... 

Scheme 8.1 Chemoenzymatic synthesis of (S)-2-hydroxy-2-methylhutyric acid by using the docking protecting group concept...

Stereoselective catalysis using biocatalysts (e.g. enzymes) and also of rationally designed small chiral molecules, deals essentially with the same principle the spatial and selective docking of guest molecules to a chiral host molecule to form complementary interactions to form reversible transient molecule associates (see the specific sections in this volume). The enantiomeric excess of a certain reaction and hence the result will be determined by the degree of chiral discrimination. Along the same theoretical lines the concepts of protein (enzyme, antibody, etc.) mimicks via imprinted" synthetic polymers should be mentioned and will be discussed further. 

Virtual screening often benefits from an expert bias which helps focus on more desirable results, given in the form of additional information. A point in case is docking under pharmacophore constraints [37] or the concept of relative pharmacophores with a special internal reference point [38]. Yet another application for a directionally biased compound comparison is the selection of chemical reagents where functional attachment points are aligned and pharmacopho-ric features are examined relative to this point of reference by a procedure termed GaP [39]. Other concepts which try to describe combinatorial products in terms of their educts and need a special reference point are shape-based To-pomers [24] and pharmacophore based OsPreys [40]. 

Some force fields and docking procedures work with the concept of essential hydrogens, i.e., hydrogens bonded to heteroatoms or hydrogens that could be involved in formation of a hydrogen bond. It is important to adhere to the procedure used to calibrate the docking program and to apply the correct method of protonation. 

Rarey, M., Kramer, B., and Lengauer, T. (1999) The particle concept placing discrete water molecules during protein-ligand docking predictions. Proteins 34,17-28. 

Figure 5. Stereospecific hydroxylation of cyclopentane carboxylic acid (a) and 4-methyl-2-pentanone (b) by two fungus species using the docking/protecting group concept.

This chapter focuses on the application of molecular modeling to calculate, manipulate, and predict protein structures and functions. Concepts of structure similarity/ overlap, homology modeling, and molecular docking, which are special concerns of protein biochemists, are considered. Approaches to protein modeling by the use of two programs (Swiss-Pdb Viewer and KineMage) and two online servers (B and CE) are described. 

The Particle Concept Placing Discrete Water Molecules During Protein-Ligand Docking Predictions. 

---