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Application of a simple quantum chemical approach to ligand fragment scoring for Trypanosoma brucei pteridine reductase 1 inhibition
- Source :
- Journal of Computer-Aided Molecular Design
- Publication Year :
- 2016
-
Abstract
- There is a need for improved and generally applicable scoring functions for fragment-based approaches to ligand design. Here, we evaluate the performance of a computationally efficient model for inhibitory activity estimation, which is composed only of multipole electrostatic energy and dispersion energy terms that approximate long-range ab initio quantum mechanical interaction energies. We find that computed energies correlate well with inhibitory activity for a compound series with varying substituents targeting two subpockets of the binding site of Trypanosoma brucei pteridine reductase 1. For one subpocket, we find that the model is more predictive for inhibitory activity than the ab initio interaction energy calculated at the MP2 level. Furthermore, the model is found to outperform a commonly used empirical scoring method. Finally, we show that the results for the two subpockets can be combined, which suggests that this simple nonempirical scoring function could be applied in fragment–based drug design. Electronic supplementary material The online version of this article (doi:10.1007/s10822-017-0035-4) contains supplementary material, which is available to authorized users.
- Subjects :
- Models, Molecular
Stereochemistry
Static Electricity
Trypanosoma brucei brucei
Ab initio
Trypanosoma brucei
010402 general chemistry
Ligands
01 natural sciences
Binding affinity prediction
Article
Structure-Activity Relationship
Computational chemistry
0103 physical sciences
Drug Discovery
Static electricity
Pteridine reductase 1
Structure–activity relationship
Molecule
Humans
Nonempirical model
Physical and Theoretical Chemistry
Binding site
PTR1
Interaction energy
Binding Sites
010304 chemical physics
biology
Molecular Structure
Ligand
Chemistry
biology.organism_classification
Trypanocidal Agents
0104 chemical sciences
Computer Science Applications
Drug Design
Quantum Theory
Oxidoreductases
Protein Binding
Subjects
Details
- ISSN :
- 15734951
- Volume :
- 31
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of computer-aided molecular design
- Accession number :
- edsair.doi.dedup.....daeb6d450dfea255e47e800ea9917657