Drug Repositioning for Noonan and LEOPARD Syndromes by Integrating Transcriptomics With a Structure-Based Approach

Frontiers in Pharmacology
Liyuan ZhuZhichao Liu

Abstract

Noonan and LEOPARD syndromes (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organs and systems including hypertrophic cardiomyopathy and dysmorphic facial features. There are no approved drugs for these two rare diseases, but it is known that a missense mutation in PTPN11 genes is associated with approximately 50% and 70% of NS and LS cases, respectively. In this study, we implemented a hybrid computational drug repositioning framework by integrating transcriptomic and structure-based approaches to explore potential treatment options for NS and LS. Specifically, disease signatures were derived from the transcriptomic profiles of human induced pluripotent stem cells (iPSCs) from NS and LS patients and reverse correlated to drug transcriptomic signatures from CMap and L1000 projects on the basis that if disease and drug transcriptomic signatures are reversely correlated, the drug has the potential to treat that disease. The compounds that were ranked top based on their transcriptomic profiles were docked to mutated and wild-type 3D structures of PTPN11 by an adjusted Induced Fit Docking (IFD) protocol. In addition, we prioritized repositioned candidates for NS and ...Continue Reading

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Citations

Mar 11, 2021·Cardiovascular Drugs and Therapy·Jae-Sung YiAnton M Bennett

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Datasets Mentioned

BETA
GSE54538
GSE20473
GSE89714
GSE32453
GSE68316
GSE36961

Methods Mentioned

BETA
transgenic
chip

Software Mentioned

Glide
Cytoscape
PICTAR2
miRBridge
RNAhybrid
miRNAMap
ApconiX
MatchSite
LigPrep
Prime

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