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Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation

Xu, Yongtao ; Fan, Baoyi ; Gao, Yunlong ; Chen, Yifan ; Han, Di ; Lu, Jiarui ; Liu, Taigang ; Gao, Qinghe ; Zhang, John Zenghui and Wang, Meiting LU (2022) In Molecules 27(23).
Abstract

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, (Formula presented.) = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, (Formula presented.) = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the... (More)

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, (Formula presented.) = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, (Formula presented.) = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
3D-QSAR, LSD1 inhibitors, molecular docking, molecular dynamics simulations
in
Molecules
volume
27
issue
23
article number
8358
publisher
MDPI AG
external identifiers
  • pmid:36500451
  • scopus:85143583163
ISSN
1420-3049
DOI
10.3390/molecules27238358
language
English
LU publication?
yes
id
bfffa41d-d2ac-4524-8dca-f7975ac1009f
date added to LUP
2022-12-23 09:08:25
date last changed
2024-04-16 19:11:04
@article{bfffa41d-d2ac-4524-8dca-f7975ac1009f,
  abstract     = {{<p>Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q<sup>2</sup> = 0.778, (Formula presented.) = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q<sup>2</sup> = 0.764, (Formula presented.) = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.</p>}},
  author       = {{Xu, Yongtao and Fan, Baoyi and Gao, Yunlong and Chen, Yifan and Han, Di and Lu, Jiarui and Liu, Taigang and Gao, Qinghe and Zhang, John Zenghui and Wang, Meiting}},
  issn         = {{1420-3049}},
  keywords     = {{3D-QSAR; LSD1 inhibitors; molecular docking; molecular dynamics simulations}},
  language     = {{eng}},
  number       = {{23}},
  publisher    = {{MDPI AG}},
  series       = {{Molecules}},
  title        = {{Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation}},
  url          = {{http://dx.doi.org/10.3390/molecules27238358}},
  doi          = {{10.3390/molecules27238358}},
  volume       = {{27}},
  year         = {{2022}},
}