Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors
Abstract
:1. Introduction
2. Methods
2.1. Assembly of the Dataset of RIPK1 Inhibitors
2.2. Preparation of Compound Structures for QSAR
2.3. Molecular Descriptors, Morgan Fingerprints, Protein-Ligand Interaction Fingerprints (PLIFs), and PLIFs Similarity
2.4. Molecular Docking Protocol Validation and Optimisation
2.5. Development of a QSAR Model of RIPK1 Inhibition Using Machine Learning
2.6. Virtual Screening and Compound Selection
2.7. Phenotypic Assay of Necroptosis Inhibition
2.8. Biochemical Assay of RIPK1 Inhibition
2.9. Performance Evaluation
2.10. Applicability Domain
2.11. Analysis of Chemical Novelty for In Silico Hit Compounds
2.12. Data Analysis and Visualisation
3. Results and Discussion
3.1. Chemical Space Analysis of RIPK1 Inhibitors
3.2. Validation of Molecular Docking Calculations
3.3. Docking Score and Ligand Efficiency Do Not Correlate with Activity
3.4. PLIFs Similarity as a New Guideline to Find RIPK1 Inhibitors
3.5. Deriving a New 4-Residue Rule to Predict RIPK1 Inhibitors
3.6. Building a Machine Learning Model to Predict Necroptosis Modulators
3.7. Virtual Screening of the ChemBridge Library Using the Docking-Based (4-Residue Signature and the PLIFs Similarity Filter) and the QSAR Models
3.8. Phenotypic Necroptosis Inhibition Assay Reveals In Silico Hits with RIPK1 Inhibitory Activity
3.9. Agreement between the Phenotypic Assay of Necroptosis Inhibition in Murine L929 Cells and the Biochemical hRIPK1 Inhibition Assay
3.10. Extracting General Structure-Activity Relationships (SAR) in New RIPK1 Inhibitors
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Aniceto, N.; Marques, V.; Amaral, J.D.; Serra, P.A.; Moreira, R.; Rodrigues, C.M.P.; Guedes, R.C. Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors. Molecules 2022, 27, 4718. https://doi.org/10.3390/molecules27154718
Aniceto N, Marques V, Amaral JD, Serra PA, Moreira R, Rodrigues CMP, Guedes RC. Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors. Molecules. 2022; 27(15):4718. https://doi.org/10.3390/molecules27154718
Chicago/Turabian StyleAniceto, Natália, Vanda Marques, Joana D. Amaral, Patrícia A. Serra, Rui Moreira, Cecília M. P. Rodrigues, and Rita C. Guedes. 2022. "Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors" Molecules 27, no. 15: 4718. https://doi.org/10.3390/molecules27154718