Ligand multiple binding modes

A different example is provided by a set of elastase inhibitors. These ligands are also related by continuous SARs. This is reflected by the presence of highly potent inhibitors with diverse structures and, in addition, structurally similar ligands that display only minor potency differences. However, in contrast to factor Xa, 3D analysis reveals a more complex picture. Specifically, elastase accepts multiple binding modes, each of which is adopted by structurally... 

In 1984 the crystal structures of (Ti(OPr )2(OC(ONHCH2Ph))2)2 (52) and (Ti(OEt)(OC-(OEt))2)(ON(Ph)CPh))2 (53) were determined 576 Since then the propensity of the tartrate ligand to adopt multiple binding modes was confirmed by a number of other crystal structures 577... 

Molecular analyses are imperfect in that serendipitous binding modes are always possible. For instance, crystal structures of PXR show that ligands have multiple binding modes [50], and protein kinases can adopt multiple inactive conformations that are druggable [51]. A dramatic example is shown in Figure 2.1, where a small modification to a non-selective kinase inhibitor yielded I400x se-... 

P. Kallblad, R. L. Mancera and N. P. Todorov, Assessment of multiple binding modes in ligand-protein docking,/. Med. Chem., 2004,47, 3334-3337. 

Stjemschantz E, Oostenbrink C (2010) Improved ligand-protein binding affinity predictions using multiple binding modes. Biophys J 98(11) 2682 2691. doi 10.1016/j.bpj.2010.02.034... 

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