Binding pose

In this section, a number of case studies (Table 5) in which different types of VS methods are combined into a hybrid workflow. Often these combine a fast, ligand or pharmacophore-based method with a later docking method. The latter is useful at the inspection stage as it allows the molecule to be reviewed within the context of the protein binding site. A poor binding pose can be an indicator of a poor fit. Furthermore, possible interactions outside the scope of the molecules used to train the ligand-based method can be identified. 

Application of Protein-Ligand NOE Matching to the Rapid Evaluation of Fragment Binding Poses... 

The NOE matching protocol is described pictorially in Figure 5.1. Two files are needed for input an experimental NOE peak list with ligand protons assigned and a set of trial binding poses to be evaluated or scored. The list of experimental peaks is typically derived from a 3D 13C-edited, 13C/15N-filtered HSQC-NOESY spectrum.1116-201 (Hereafter, this type of spectrum will be referred to as a 3D X-filtered NOESY spectrum.)... 

Constantine, K. L., Davis, M. E., Metzler, W. J., Mueller, L. and Claus, B. L. (2006). Protein-ligand NOE matching a high-throughput method for binding pose evaluation that does not require protein NMR resonance assignments. J. Am. Chem. Soc. 128, 7252-7263. 

Baxter et al. have nicely demonstrated that one can take a 0.9 xM hit, discovered from HTS, to an 11 nM K compound.1341 An X-ray crystal structure of the HTS lead helped demonstrate the unique binding pose in the active site which only occupied the non prime side of BACE-1 in a hairpin orientation. The crystal structure revealed that the prime side was not occupied and the incorporation of a cyclohexyl ring resulted in a potent 11 nM compound.1331... 

Since the discovery of the therapeutic potential of tubulin targeting drugs, there has been a demand for structural information at the molecular level about the binding pose of the small-molecule ligands, very much needed by the medicinal chemists for the rational design of novel derivatives. Even nowadays, near-atomic resolution structures are available only for a few tubulin binders, namely, the EC-derived structures of the MT-stabilizers PTX [11] and EpoA [26], and the X-ray structures of complexes of tubulin/RB3-SLD with the MT-destabilizers colchicine [12] and vinblastine [13]. 

For the structure calculation, 5000 binding poses of EpoA were generated by non-restraint docking of its NMR-derived conformation into the binding site of the EC-derived 3D structure of tubulin (complex TB). The docking protocol was designed to sample tubulin conformations that differed from the starting EC-derived... 

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