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Benchmarking of protein descriptor sets in proteochemometric modeling (part 2): modeling performance of 13 amino acid descriptor sets.

ABSTRACT: BACKGROUND: While a large body of work exists on comparing and benchmarking descriptors of molecular structures, a similar comparison of protein descriptor sets is lacking. Hence, in the current work a total of 13 amino acid descriptor sets have been benchmarked with respect to their ability of establishing bioactivity models. The descriptor sets included in the study are Z-scales (3 variants), VHSE, T-scales, ST-scales, MS-WHIM, FASGAI, BLOSUM, a novel protein descriptor set (termed ProtFP (4 variants)), and in addition we created and benchmarked three pairs of descriptor combinations. Prediction performance was evaluated in seven structure-activity benchmarks which comprise Angiotensin Converting Enzyme (ACE) dipeptidic inhibitor data, and three proteochemometric data sets, namely (1) GPCR ligands modeled against a GPCR panel, (2) enzyme inhibitors (NNRTIs) with associated bioactivities against a set of HIV enzyme mutants, and (3) enzyme inhibitors (PIs) with associated bioactivities on a large set of HIV enzyme mutants. RESULTS: The amino acid descriptor sets compared here show similar performance (<0.1 log units RMSE difference and <0.1 difference in MCC), while errors for individual proteins were in some cases found to be larger than those resulting from descriptor set differences ( > 0.3 log units RMSE difference and >0.7 difference in MCC). Combining different descriptor sets generally leads to better modeling performance than utilizing individual sets. The best performers were Z-scales (3) combined with ProtFP (Feature), or Z-Scales (3) combined with an average Z-Scale value for each target, while ProtFP (PCA8), ST-Scales, and ProtFP (Feature) rank last. CONCLUSIONS: While amino acid descriptor sets capture different aspects of amino acids their ability to be used for bioactivity modeling is still - on average - surprisingly similar. Still, combining sets describing complementary information consistently leads to small but consistent improvement in modeling performance (average MCC 0.01 better, average RMSE 0.01 log units lower). Finally, performance differences exist between the targets compared thereby underlining that choosing an appropriate descriptor set is of fundamental for bioactivity modeling, both from the ligand- as well as the protein side.

SUBMITTER: van Westen GJ

PROVIDER: S-EPMC4015169 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Benchmarking of protein descriptor sets in proteochemometric modeling (part 2): modeling performance of 13 amino acid descriptor sets.

van Westen Gerard Jp GJ Swier Remco F RF Cortes-Ciriano Isidro I Wegner Jörg K JK Overington John P JP Ijzerman Adriaan P AP van Vlijmen Herman Wt HW Bender Andreas A

Journal of cheminformatics 20130924 1

<h4>Background</h4>While a large body of work exists on comparing and benchmarking descriptors of molecular structures, a similar comparison of protein descriptor sets is lacking. Hence, in the current work a total of 13 amino acid descriptor sets have been benchmarked with respect to their ability of establishing bioactivity models. The descriptor sets included in the study are Z-scales (3 variants), VHSE, T-scales, ST-scales, MS-WHIM, FASGAI, BLOSUM, a novel protein descriptor set (termed Prot ...[more]

PMID: 24059743

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Project description:Affinity fingerprints report the activity of small molecules across a set of assays, and thus permit to gather information about the bioactivities of structurally dissimilar compounds, where models based on chemical structure alone are often limited, and model complex biological endpoints, such as human toxicity and in vitro cancer cell line sensitivity. Here, we propose to model in vitro compound activity using computationally predicted bioactivity profiles as compound descriptors. To this aim, we apply and validate a framework for the calculation of QSAR-derived affinity fingerprints (QAFFP) using a set of 1360 QSAR models generated using Ki, Kd, IC50 and EC50 data from ChEMBL database. QAFFP thus represent a method to encode and relate compounds on the basis of their similarity in bioactivity space. To benchmark the predictive power of QAFFP we assembled IC50 data from ChEMBL database for 18 diverse cancer cell lines widely used in preclinical drug discovery, and 25 diverse protein target data sets. This study complements part 1 where the performance of QAFFP in similarity searching, scaffold hopping, and bioactivity classification is evaluated. Despite being inherently noisy, we show that using QAFFP as descriptors leads to errors in prediction on the test set in the ~ 0.65-0.95 pIC50 units range, which are comparable to the estimated uncertainty of bioactivity data in ChEMBL (0.76-1.00 pIC50 units). We find that the predictive power of QAFFP is slightly worse than that of Morgan2 fingerprints and 1D and 2D physicochemical descriptors, with an effect size in the 0.02-0.08 pIC50 units range. Including QSAR models with low predictive power in the generation of QAFFP does not lead to improved predictive power. Given that the QSAR models we used to compute the QAFFP were selected on the basis of data availability alone, we anticipate better modeling results for QAFFP generated using more diverse and biologically meaningful targets. Data sets and Python code are publicly available at https://github.com/isidroc/QAFFP_regression .

Dataset Information

Benchmarking of protein descriptor sets in proteochemometric modeling (part 2): modeling performance of 13 amino acid descriptor sets.

Publications

Benchmarking of protein descriptor sets in proteochemometric modeling (part 2): modeling performance of 13 amino acid descriptor sets.

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