Dataset Information

QSAR Development for Plasma Protein Binding: Influence of the Ionization State.

ABSTRACT:

Purpose

This study explored several strategies to improve the performance of literature QSAR models for plasma protein binding (PPB), such as a suitable endpoint transformation, a correct representation of chemicals, more consistency in the dataset, and a reliable definition of the applicability domain.

Methods

We retrieved human fraction unbound (Fu) data for 670 compounds from the literature and carefully checked them for consistency. Descriptors were calculated taking account of the ionization state of molecules at physiological pH (7.4), in order to better estimate the affinity of molecules to blood proteins. We used different algorithms and chemical descriptors to explore the most suitable strategy for modeling the endpoint. SMILES (simplified molecular input line entry system)-based string descriptors were also tested with the CORAL software (CORelation And Logic). We did an outlier analysis to establish the models to use (or not to use) in case of well recognized families.

Results

Internal validation of the selected models returned Q² values close to 0.60. External validation also gave r² values always greater than 0.60. The CORAL descriptor based model for ?fu was the best, with r² 0.74 in external validation.

Conclusions

Performance in prediction confirmed the robustness of all the derived models and their suitability for real-life purposes, i.e. screening chemicals for their ADMET profiling. Optimization of descriptors can be useful in order to obtain the correct results with a ionized molecule.

SUBMITTER: Toma C

PROVIDER: S-EPMC6308215 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

QSAR Development for Plasma Protein Binding: Influence of the Ionization State.

Toma Cosimo C Gadaleta Domenico D Roncaglioni Alessandra A Toropov Andrey A Toropova Alla A Marzo Marco M Benfenati Emilio E

Pharmaceutical research 20181227 2

<h4>Purpose</h4>This study explored several strategies to improve the performance of literature QSAR models for plasma protein binding (PPB), such as a suitable endpoint transformation, a correct representation of chemicals, more consistency in the dataset, and a reliable definition of the applicability domain.<h4>Methods</h4>We retrieved human fraction unbound (Fu) data for 670 compounds from the literature and carefully checked them for consistency. Descriptors were calculated taking account o ...[more]

PMID: 30591975

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Project description:This work investigates statistical prevalence and overall physical origins of changes in charge states of receptor proteins upon ligand binding. These changes are explored as a function of the ligand type (small molecule, protein, and nucleic acid), and distance from the binding region. Standard continuum solvent methodology is used to compute, on an equal footing, pK changes upon ligand binding for a total of 5899 ionizable residues in 20 protein-protein, 20 protein-small molecule, and 20 protein-nucleic acid high-resolution complexes. The size of the data set combined with an extensive error and sensitivity analysis allows us to make statistically justified and conservative conclusions: in 60% of all protein-small molecule, 90% of all protein-protein, and 85% of all protein-nucleic acid complexes there exists at least one ionizable residue that changes its charge state upon ligand binding at physiological conditions (pH = 6.5). Considering the most biologically relevant pH range of 4-8, the number of ionizable residues that experience substantial pK changes (DeltapK > 1.0) due to ligand binding is appreciable: on average, 6% of all ionizable residues in protein-small molecule complexes, 9% in protein-protein, and 12% in protein-nucleic acid complexes experience a substantial pK change upon ligand binding. These changes are safely above the statistical false-positive noise level. Most of the changes occur in the immediate binding interface region, where approximately one out of five ionizable residues experiences substantial pK change regardless of the ligand type. However, the physical origins of the change differ between the types: in protein-nucleic acid complexes, the pK values of interface residues are predominantly affected by electrostatic effects, whereas in protein-protein and protein-small molecule complexes, structural changes due to the induced-fit effect play an equally important role. In protein-protein and protein-nucleic acid complexes, there is a statistically significant number of substantial pK perturbations, mostly due to the induced-fit structural changes, in regions far from the binding interface.

Dataset Information

QSAR Development for Plasma Protein Binding: Influence of the Ionization State.

Purpose

Methods

Results

Conclusions

Publications

QSAR Development for Plasma Protein Binding: Influence of the Ionization State.

Similar Datasets

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