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Predicting binding affinity of CSAR ligands using both structure-based and ligand-based approaches.

ABSTRACT: We report on the prediction accuracy of ligand-based (2D QSAR) and structure-based (MedusaDock) methods used both independently and in consensus for ranking the congeneric series of ligands binding to three protein targets (UK, ERK2, and CHK1) from the CSAR 2011 benchmark exercise. An ensemble of predictive QSAR models was developed using known binders of these three targets extracted from the publicly available ChEMBL database. Selected models were used to predict the binding affinity of CSAR compounds toward the corresponding targets and rank them accordingly; the overall ranking accuracy evaluated by Spearman correlation was as high as 0.78 for UK, 0.60 for ERK2, and 0.56 for CHK1, placing our predictions in the top 10% among all the participants. In parallel, MedusaDock, designed to predict reliable docking poses, was also used for ranking the CSAR ligands according to their docking scores; the resulting accuracy (Spearman correlation) for UK, ERK2, and CHK1 were 0.76, 0.31, and 0.26, respectively. In addition, performance of several consensus approaches combining MedusaDock- and QSAR-predicted ranks altogether has been explored; the best approach yielded Spearman correlation coefficients for UK, ERK2, and CHK1 of 0.82, 0.50, and 0.45, respectively. This study shows that (i) externally validated 2D QSAR models were capable of ranking CSAR ligands at least as accurately as more computationally intensive structure-based approaches used both by us and by other groups and (ii) ligand-based QSAR models can complement structure-based approaches by boosting the prediction performances when used in consensus.

SUBMITTER: Fourches D

PROVIDER: S-EPMC3779696 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Predicting binding affinity of CSAR ligands using both structure-based and ligand-based approaches.

Fourches Denis D Muratov Eugene E Ding Feng F Dokholyan Nikolay V NV Tropsha Alexander A

Journal of chemical information and modeling 20130717 8

We report on the prediction accuracy of ligand-based (2D QSAR) and structure-based (MedusaDock) methods used both independently and in consensus for ranking the congeneric series of ligands binding to three protein targets (UK, ERK2, and CHK1) from the CSAR 2011 benchmark exercise. An ensemble of predictive QSAR models was developed using known binders of these three targets extracted from the publicly available ChEMBL database. Selected models were used to predict the binding affinity of CSAR c ...[more]

PMID: 23809015

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Project description:Protein mutations, especially those which occur in the binding site, play an important role in inter-individual drug response and may alter binding affinity and thus impact the drug's efficacy and side effects. Unfortunately, large-scale experimental screening of ligand-binding against protein variants is still time-consuming and expensive. Alternatively, in silico approaches can play a role in guiding those experiments. Methods ranging from computationally cheaper machine learning (ML) to the more expensive molecular dynamics have been applied to accurately predict the mutation effects. However, these effects have been mostly studied on limited and small datasets, while ideally a large dataset of binding affinity changes due to binding site mutations is needed. In this work, we used the PSnpBind database with six hundred thousand docking experiments to train a machine learning model predicting protein-ligand binding affinity for both wild-type proteins and their variants with a single-point mutation in the binding site. A numerical representation of the protein, binding site, mutation, and ligand information was encoded using 256 features, half of them were manually selected based on domain knowledge. A machine learning approach composed of two regression models is proposed, the first predicting wild-type protein-ligand binding affinity while the second predicting the mutated protein-ligand binding affinity. The best performing models reported an RMSE value within 0.5 [Formula: see text] 0.6 kcal/mol-1 on an independent test set with an R2 value of 0.87 [Formula: see text] 0.90. We report an improvement in the prediction performance compared to several reported models developed for protein-ligand binding affinity prediction. The obtained models can be used as a complementary method in early-stage drug discovery. They can be applied to rapidly obtain a better overview of the ligand binding affinity changes across protein variants carried by people in the population and narrow down the search space where more time-demanding methods can be used to identify potential leads that achieve a better affinity for all protein variants.

Dataset Information

Predicting binding affinity of CSAR ligands using both structure-based and ligand-based approaches.

Publications

Predicting binding affinity of CSAR ligands using both structure-based and ligand-based approaches.

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