Antiangiogenic activity and in silico cereblon binding analysis of novel thalidomide analogs

Megan L. Peach; Shaunna L. Beedie; Cindy H. Chau; Matthew K. Collins; Suzana Markolovic; Weiming Luo; David Tweedie; Christian Steinebach; Nigel H. Greig; Michael Gütschow; Neil Vargesson; Marc C. Nicklaus; William D. Figg

doi:10.3390/molecules25235683

Antiangiogenic activity and in silico cereblon binding analysis of novel thalidomide analogs

Megan L. Peach, Shaunna L. Beedie, Cindy H. Chau, Matthew K. Collins, Suzana Markolovic, Weiming Luo, David Tweedie, Christian Steinebach, Nigel H. Greig, Michael Gütschow, Neil Vargesson, Marc C. Nicklaus, William D. Figg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

Original language	English
Article number	5683
Journal	Molecules
Volume	25
Issue number	23
DOIs	https://doi.org/10.3390/molecules25235683
State	Published - 1 Dec 2020
Externally published	Yes

Keywords

Angiogenesis
Cereblon
Docking
Structure–activity relationships
Thalidomide

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10.3390/molecules25235683

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@article{b8838eb46e6c45e9b582d1fc7577edd4,

title = "Antiangiogenic activity and in silico cereblon binding analysis of novel thalidomide analogs",

abstract = "Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.",

keywords = "Angiogenesis, Cereblon, Docking, Structure–activity relationships, Thalidomide",

author = "Peach, {Megan L.} and Beedie, {Shaunna L.} and Chau, {Cindy H.} and Collins, {Matthew K.} and Suzana Markolovic and Weiming Luo and David Tweedie and Christian Steinebach and Greig, {Nigel H.} and Michael G{\"u}tschow and Neil Vargesson and Nicklaus, {Marc C.} and Figg, {William D.}",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = dec,

day = "1",

doi = "10.3390/molecules25235683",

language = "English",

volume = "25",

journal = "Molecules",

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T1 - Antiangiogenic activity and in silico cereblon binding analysis of novel thalidomide analogs

AU - Peach, Megan L.

AU - Beedie, Shaunna L.

AU - Chau, Cindy H.

AU - Collins, Matthew K.

AU - Markolovic, Suzana

AU - Luo, Weiming

AU - Tweedie, David

AU - Steinebach, Christian

AU - Greig, Nigel H.

AU - Gütschow, Michael

AU - Vargesson, Neil

AU - Nicklaus, Marc C.

AU - Figg, William D.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

AB - Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

KW - Angiogenesis

KW - Cereblon

KW - Docking

KW - Structure–activity relationships

KW - Thalidomide

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U2 - 10.3390/molecules25235683

DO - 10.3390/molecules25235683

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SN - 1420-3049

VL - 25

JO - Molecules

JF - Molecules

IS - 23

M1 - 5683

ER -

Antiangiogenic activity and in silico cereblon binding analysis of novel thalidomide analogs

Abstract

Keywords

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