Virtual screening against highly charged active sites: identifying substrates of alpha-beta barrel enzymes
| Autor: | Matthew P. Jacobson, Chakrapani Kalyanaraman, Katarzyna Bernacki |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Ammonia-Lyases
Stereochemistry Static Electricity Racemases and Epimerases Ligands Biochemistry Protein Structure Secondary Substrate Specificity Protein structure Apoenzymes Computational chemistry Binding site Carbon-Carbon Lyases Intramolecular Lyases Amino Acid Isomerases Virtual screening Binding Sites biology Chemistry Enolase superfamily Escherichia coli Proteins Alanine Racemase Active site Computational Biology Chemical similarity Beta barrel Docking (molecular) Phosphopyruvate Hydratase biology.protein Holoenzymes Algorithms |
| Zdroj: | Biochemistry. 44(6) |
| ISSN: | 0006-2960 |
| Popis: | We have developed a virtual ligand screening method designed to help assign enzymatic function for alpha-beta barrel proteins. We dock a library of approximately 19,000 known metabolites against the active site and attempt to identify the relevant substrate based on predicted relative binding free energies. These energies are computed using a physics-based energy function based on an all-atom force field (OPLS-AA) and a generalized Born implicit solvent model. We evaluate the ability of this method to identify the known substrates of several members of the enolase superfamily of enzymes, including both holo and apo structures (11 total). The active sites of these enzymes contain numerous charged groups (lysines, carboxylates, histidines, and one or more metal ions) and thus provide a challenge for most docking scoring functions, which treat electrostatics and solvation in a highly approximate manner. Using the physics-based scoring procedure, the known substrate is ranked within the top 6% of the database in all cases, and in 8 of 11 cases, it is ranked within the top 1%. Moreover, the top-ranked ligands are strongly enriched in compounds with high chemical similarity to the substrate (e.g., different substitution patterns on a similar scaffold). These results suggest that our method can be used, in conjunction with other information including genomic context and known metabolic pathways, to suggest possible substrates or classes of substrates for experimental testing. More broadly, the physics-based scoring method performs well on highly charged binding sites and is likely to be useful in inhibitor docking against polar binding sites as well. The method is fast ( |
| Databáze: | OpenAIRE |
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