Modeling enzyme-ligand binding in drug discovery

Abstract

Enzymes are one of the most important groups of drug targets, and identifying possible ligand-enzyme interactions is of major importance in many drug discovery processes. Novel computational methods have been developed that can apply the information from the increasing number of resolved and available ligand-enzyme complexes to model new unknown interactions and therefore contribute to answer open questions in the field of drug discovery like the identification of unknown protein functions, off-target binding, ligand 3D homology modeling and induced-fit simulations.

Keywords: Drug repositioning; Induced-fit simulations; Ligand 3D homolgy modeling; Off-target binding; ProBiS-ligands web server; Unknown protein fuctions.

Fig. 1

Flowchart of binding site comparison with subsequent ligand transposition

Fig. 2

Ligand homology modeling using ProBiS-ligands web server on the example of butyrylcholinesterase enzyme (PDB code: 4tpk). On the right side of the screen is the list of predicted ligands with their corresponding Z-scores, specificities and PDB codes of protein structures from which they were transposed. The selected ligand’s row is highlighted orange. On the left side is the Jsmol viewer that contains the three-dimensional pose of the selected predicted ligand (galantamine, sticks, violet) and the predicted binding amino-acid residues (sticks, CPK colors, black labels)