Dataset Information

A novel hybrid ultrafast shape descriptor method for use in virtual screening.

ABSTRACT:

Background

We have introduced a new Hybrid descriptor composed of the MACCS key descriptor encoding topological information and Ballester and Richards' Ultrafast Shape Recognition (USR) descriptor. The latter one is calculated from the moments of the distribution of the interatomic distances, and in this work we also included higher moments than in the original implementation.

Results

The performance of this Hybrid descriptor is assessed using Random Forest and a dataset of 116,476 molecules. Our dataset includes 5,245 molecules in ten classes from the 2005 World Anti-Doping Agency (WADA) dataset and 111,231 molecules from the National Cancer Institute (NCI) database. In a 10-fold Monte Carlo cross-validation this dataset was partitioned into three distinct parts for training, optimisation of an internal threshold that we introduced, and validation of the resulting model. The standard errors obtained were used to assess statistical significance of observed improvements in performance of our new descriptor.

Conclusion

The Hybrid descriptor was compared to the MACCS key descriptor, USR with the first three (USR), four (UF4) and five (UF5) moments, and a combination of MACCS with USR (three moments). The MACCS key descriptor was not combined with UF5, due to similar performance of UF5 and UF4. Superior performance in terms of all figures of merit was found for the MACCS/UF4 Hybrid descriptor with respect to all other descriptors examined. These figures of merit include recall in the top 1% and top 5% of the ranked validation sets, precision, F-measure, area under the Receiver Operating Characteristic curve and Matthews Correlation Coefficient.

SUBMITTER: Cannon EO

PROVIDER: S-EPMC2275267 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Publications

A novel hybrid ultrafast shape descriptor method for use in virtual screening.

Cannon Edward O EO Nigsch Florian F Mitchell John B O JB

Chemistry Central journal 20080218

<h4>Background</h4>We have introduced a new Hybrid descriptor composed of the MACCS key descriptor encoding topological information and Ballester and Richards' Ultrafast Shape Recognition (USR) descriptor. The latter one is calculated from the moments of the distribution of the interatomic distances, and in this work we also included higher moments than in the original implementation.<h4>Results</h4>The performance of this Hybrid descriptor is assessed using Random Forest and a dataset of 116,47 ...[more]

PMID: 18282294

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Project description:The antagonist-bound crystal structure of the nociceptin receptor (NOP), from the opioid receptor family, was recently reported along with those of the other opioid receptors bound to opioid antagonists. We recently reported the first homology model of the 'active-state' of the NOP receptor, which when docked with 'agonist' ligands showed differences in the TM helices and residues, consistent with GPCR activation after agonist binding. In this study, we explored the use of the active-state NOP homology model for structure-based virtual screening to discover NOP ligands containing new chemical scaffolds. Several NOP agonist and antagonist ligands previously reported are based on a common piperidine scaffold. Given the structure-activity relationships for known NOP ligands, we developed a hybrid method that combines a structure-based and ligand-based approach, utilizing the active-state NOP receptor as well as the pharmacophoric features of known NOP ligands, to identify novel NOP binding scaffolds by virtual screening. Multiple conformations of the NOP active site including the flexible second extracellular loop (EL2) loop were generated by simulated annealing and ranked using enrichment factor (EF) analysis and a ligand-decoy dataset containing known NOP agonist ligands. The enrichment factors were further improved by combining shape-based screening of this ligand-decoy dataset and calculation of consensus scores. This combined structure-based and ligand-based EF analysis yielded higher enrichment factors than the individual methods, suggesting the effectiveness of the hybrid approach. Virtual screening of the CNS Permeable subset of the ZINC database was carried out using the above-mentioned hybrid approach in a tiered fashion utilizing a ligand pharmacophore-based filtering step, followed by structure-based virtual screening using the refined NOP active-state models from the enrichment analysis. Determination of the NOP receptor binding affinity of a selected set of top-scoring hits resulted in identification of several compounds with measurable binding affinity at the NOP receptor, one of which had a new chemotype for NOP receptor binding. The hybrid ligand-based and structure-based methodology demonstrates an effective approach for virtual screening that leverages existing SAR and receptor structure information for identifying novel hits for NOP receptor binding. The refined active-state NOP homology models obtained from the enrichment studies can be further used for structure-based optimization of these new chemotypes to obtain potent and selective NOP receptor ligands for therapeutic development.

Dataset Information

A novel hybrid ultrafast shape descriptor method for use in virtual screening.

Background

Results

Conclusion

Publications

A novel hybrid ultrafast shape descriptor method for use in virtual screening.

Similar Datasets

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