Cocrystallized ligands

Figure4.10 Superimposition of protein kinase A structures Istc (green) and IqSu (red) together with their cocrystallized ligands staurosporine (blue) and (S)-2-methyl-l-[(4-methyl-5-isoquinoline) sulfonyl]- homopipera-...

In the Pfizer in-house IC50 data set, there are 1059 pairs of compounds consisting of a carboxylic add and the equivalent tetrazole that have been tested in the same assay. In order to define a binding environment for the acid/tetrazole, an attempt was made to map each pair to its most relevant pocket in the PDB ligand database by identifying the most similar cocrystallized ligand in a protein from the same family. 

Finally, the tris(pyrazolyl)hydroborato ligand system has also provided an interesting example in which a crystallographic site is disordered between a vacancy and a chain of three atoms. Thus, the x-ray structure of the cobalt complex [TpAnt]CoNCS (Ant = 9-anthryl) revealed the presence of the cocrystallized thallium derivative... 

TpAnt]Tl, and that the composition of the crystal studied was approximately [TpAnt](CoNCS)0.94TI0.06. As a consequence of the cocrystallization, the crystallographic site occupied by the CoNCS moiety was disordered with a thallium atom (Fig. 57). The ability of [TpAnt]CoNCS and [TpAnt]Tl, which differ substantially in the number of atoms at the disordered site, to cocrystallize is presumably due to the fact that the disordered site is enclosed within the pocket that is provided by the tris(pyrazolyl)hydroborato ligand. 

Fig. 57. Cocrystallized [TpAnt]CoNCS and [TpAnt]Tl. Reprinted from Polyhedron, 14, Han, R., Parkin, G., and Trofimenko, S The tris[3-(9-anthryl)pyrazol-l-yl]hydroborato ligand, [TpAnt] Compositional disorder between a vacancy and a chain of three atoms, p. 387, copyright 1995, with kind permission from Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington 0X5 1GB, UK.

There are six crystal structures reported in the Protein Data Bank two without ligand (ltqnand IwOe), one cocrystallized with progesterone (7) (IwOf), one with mytrapone (8) (IwOg), one with ketoconazole (9) (2j0c) and one with erythromycin (10) (2j0d). 

Fig. 5.5 Putative interactions of the cocrystallized selective Cox2 ligand SC-558 with its active site, assuming a neutral sulfonamide group - the state used to assign pharmacophore feature flags by the used software. Dotted lines stand for hydrogen bonds, the other residues being responsible for hydrophobic contacts. From a physicochemical point of view, an ionized SO2 NH involved in a salt bridge with Arg 513 and hydrogen bonding to the other tautomer of His 90 would make more sense.

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