While structural genomics resulted in thousands of new protein crystal structures, we still do not know the functions of most of these proteins. One reason for this shortcoming is their unique sequences or folds, which leaves them assigned as proteins of ‘unknown function’. Recent advances in and applications of cutting edge binding site comparison algorithms for binding site detection and function prediction have begun to shed light on this problem. Here, we review these algorithms and their use in function prediction and pharmaceutical discovery. Finding common binding sites in weakly related proteins may lead to the discovery of new protein functions and to novel ways of drug discovery.
COBISS.SI-ID: 5395738
The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query proteinu. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands and http://probis.nih.gov/ligands.
COBISS.SI-ID: 5514010
Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally,compound 1 inhibited amyloid 1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 M), and protected cultured SH-SY5Y cells against amyloid-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.
COBISS.SI-ID: 3713393