Abstract
SummaryThere are numerous applications that use the structures of protein-ligand complexes from the PDB, such as 3D pharmacophore identification, virtual screening, and fragment-based drug design. The structures underlying these applications are potentially much more informative if they contain biologically relevant bound ligands, with high similarity to the cognate ligands. We present a study of ligand-enzyme complexes that compares the similarity of bound and cognate ligands, enabling the best matches to be identified. We calculate the molecular similarity scores using a method called PARITY (proportion of atoms residing in identical topology), which can conveniently be combined to give a similarity score for all cognate reactants or products in the reaction. Thus, we generate a rank-ordered list of related PDB structures, according to the biological similarity of the ligands bound in the structures.
Highlights
Enzymes are an important group of drug targets where understanding ligand-enzyme binding requires inspection of crystal structures with bound ligands
We present a method called PARITY to compare the similarity of bound and cognate ligands and automatically annotate the current content of the PDB
A key observation is the high level of PDB structures where there are no bound ligands or that have bound ligands with low similarity to cognate ligands
Summary
Enzymes are an important group of drug targets where understanding ligand-enzyme binding requires inspection of crystal structures with bound ligands. The ligand-enzyme complex becomes more informative if the bound ligand is similar to the cognate ligand (i.e., the compound expected to bind in vivo), allowing the binding site and ligand-enzyme interactions to be identified more completely. It is often not possible to bind cognate ligands without the reaction occurring, so compounds with varying degrees of similarity to the cognate ligands are used as surrogates in co-crystallization experiments. We propose the similarity of bound and cognate small-molecule ligands as another important measure for scoring structures, where pocket identification and description would be enhanced from understanding the biological relevance of the bound substrates
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