Binding of alpha-hydroxy-beta-amino acid inhibitors to methionine aminopeptidase. The performance of two types of scoring functions

• Published in: Journal of computer-aided molecular design Vol. 17; no. 5-6; pp. 383 - 397
• Main Authors: Jørgensen, Anne Techau, Sørensen, Morten Dahl, Björkling, Fredrik, Liljefors, Tommy
• Format: Journal Article
• Language: English
• Published: Netherlands 01.05.2003
• Subjects: Algorithms; Aminopeptidases - antagonists & inhibitors; Aminopeptidases - chemistry; Aminopeptidases - metabolism; Binding Sites; Computer Simulation; Databases, Protein; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - enzymology; Humans; Ligands; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - chemistry; Metalloendopeptidases - metabolism; Methionyl Aminopeptidases; Models, Chemical; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Binding; Quantitative Structure-Activity Relationship; Thermodynamics
• ISSN: 0920-654X
• DOI: 10.1023/A:1026149810619

The binding mode of a recently described set of alpha-hydroxy-beta-amino acid inhibitors of methionine aminopeptidase type 2 is suggested in the present work. The binding mode is supported by analysis of published structures of transition state analogues co-crystallised with E. coli methionine aminopeptidase and by a comparison of molecular interaction fields calculated using GRID for E. coli and human methionine aminopeptidase. Based on the suggested binding mode two types of scoring functions have been evaluated and compared. These are the commercially available consensus score, CScore, and scoring of the ligands employing energies calculated using the Merck Molecular Force Field (MMFF). Enriched subsets of ligands were obtained when using CScore, but these scores could not be used to assess the relative affinities of individual compounds. Although still not sufficiently accurate for reliable predictive purposes, an improved correlation was obtained between structure and affinity using a combined force field energy including contributions from solvation and conformational energy penalty for binding.