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QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods
Phosphorylation of PI3Kγ as a member of lipid kinases-enzymes, plays a crucial role in regulating immune cells through the generation of intracellular signals. Deregulation of this pathway is involved in several tumors. In this research, diverse sets of potent and selective isoform-specific PI3Kγ in...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005662/ https://www.ncbi.nlm.nih.gov/pubmed/35414065 http://dx.doi.org/10.1038/s41598-022-09843-0 |
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author | Sadeghi, Fereydoun Afkhami, Abbas Madrakian, Tayyebeh Ghavami, Raouf |
author_facet | Sadeghi, Fereydoun Afkhami, Abbas Madrakian, Tayyebeh Ghavami, Raouf |
author_sort | Sadeghi, Fereydoun |
collection | PubMed |
description | Phosphorylation of PI3Kγ as a member of lipid kinases-enzymes, plays a crucial role in regulating immune cells through the generation of intracellular signals. Deregulation of this pathway is involved in several tumors. In this research, diverse sets of potent and selective isoform-specific PI3Kγ inhibitors whose drug-likeness was confirmed based on Lipinski’s rule of five were used in the modeling process. Genetic algorithm (GA)-based multivariate analysis was employed on the half-maximal inhibitory concentration (IC(50)) of them. In this way, multiple linear regression (MLR) and artificial neural network (ANN) algorithm, were used to QSAR models construction on 245 compounds with a wide range of pIC(50) (5.23–9.32). The stability and robustness of the models have been evaluated by external and internal validation methods (R(2) 0.623–0.642, RMSE 0.464–0.473, F 40.114, Q(2)(LOO) 0.600, and R(2)(y-random) 0.011). External verification using a wide variety of structures out of the training and test sets show that ANN is superior to MLR. The descriptors entered into the model are in good agreement with the X-ray structures of target-ligand complexes; so the model is interpretable. Finally, Williams plot-based analysis was applied to simultaneously compare the inhibitory activity and structural similarity of training, test and validation sets. |
format | Online Article Text |
id | pubmed-9005662 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90056622022-04-15 QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods Sadeghi, Fereydoun Afkhami, Abbas Madrakian, Tayyebeh Ghavami, Raouf Sci Rep Article Phosphorylation of PI3Kγ as a member of lipid kinases-enzymes, plays a crucial role in regulating immune cells through the generation of intracellular signals. Deregulation of this pathway is involved in several tumors. In this research, diverse sets of potent and selective isoform-specific PI3Kγ inhibitors whose drug-likeness was confirmed based on Lipinski’s rule of five were used in the modeling process. Genetic algorithm (GA)-based multivariate analysis was employed on the half-maximal inhibitory concentration (IC(50)) of them. In this way, multiple linear regression (MLR) and artificial neural network (ANN) algorithm, were used to QSAR models construction on 245 compounds with a wide range of pIC(50) (5.23–9.32). The stability and robustness of the models have been evaluated by external and internal validation methods (R(2) 0.623–0.642, RMSE 0.464–0.473, F 40.114, Q(2)(LOO) 0.600, and R(2)(y-random) 0.011). External verification using a wide variety of structures out of the training and test sets show that ANN is superior to MLR. The descriptors entered into the model are in good agreement with the X-ray structures of target-ligand complexes; so the model is interpretable. Finally, Williams plot-based analysis was applied to simultaneously compare the inhibitory activity and structural similarity of training, test and validation sets. Nature Publishing Group UK 2022-04-12 /pmc/articles/PMC9005662/ /pubmed/35414065 http://dx.doi.org/10.1038/s41598-022-09843-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sadeghi, Fereydoun Afkhami, Abbas Madrakian, Tayyebeh Ghavami, Raouf QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods |
title | QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods |
title_full | QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods |
title_fullStr | QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods |
title_full_unstemmed | QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods |
title_short | QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods |
title_sort | qsar analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (pi3kγ) inhibitors using mlr and ann methods |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005662/ https://www.ncbi.nlm.nih.gov/pubmed/35414065 http://dx.doi.org/10.1038/s41598-022-09843-0 |
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