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A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis

PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug app...

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Autores principales: Ion, George Nicolae Daniel, Nitulescu, George Mihai, Mihai, Dragos Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455354/
https://www.ncbi.nlm.nih.gov/pubmed/37629492
http://dx.doi.org/10.3390/life13081635
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author Ion, George Nicolae Daniel
Nitulescu, George Mihai
Mihai, Dragos Paul
author_facet Ion, George Nicolae Daniel
Nitulescu, George Mihai
Mihai, Dragos Paul
author_sort Ion, George Nicolae Daniel
collection PubMed
description PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates.
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spelling pubmed-104553542023-08-26 A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis Ion, George Nicolae Daniel Nitulescu, George Mihai Mihai, Dragos Paul Life (Basel) Article PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates. MDPI 2023-07-27 /pmc/articles/PMC10455354/ /pubmed/37629492 http://dx.doi.org/10.3390/life13081635 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ion, George Nicolae Daniel
Nitulescu, George Mihai
Mihai, Dragos Paul
A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis
title A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis
title_full A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis
title_fullStr A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis
title_full_unstemmed A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis
title_short A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis
title_sort pim-1 kinase inhibitor docking optimization study based on logistic regression models and interaction analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10455354/
https://www.ncbi.nlm.nih.gov/pubmed/37629492
http://dx.doi.org/10.3390/life13081635
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