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

Liyuan Zhu,Mike Mikailov,Zhichao Liu,Menghang Xia,Brian Delavan,Weida Tong,Jinghua Zhao,Ruth Roberts,Ruili Huang

doi:10.3389/fphar.2020.00927

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 LS by a consensus ranking strategy. Network analysis and phenotypic anchoring of the transcriptomic data could discriminate the two diseases at the molecular level. Furthermore, the adjusted IFD protocol was able to recapitulate the binding specificity of potential drug candidates to mutated 3D structures, revealing the relevant amino acids. Importantly, a list of potential drug candidates for repositioning was identified including 61 for NS and 43 for LS and was further verified from literature reports and on-going clinical trials. Altogether, this hybrid computational drug repositioning approach has highlighted a number of drug candidates for NS and LS and could be applied to identifying drug candidates for other diseases as well.

Highlights

Noonan syndrome (NS) and LEOPARD syndrome [LS, called Noonan syndrome with multiple lentigines (NSML)] are autosomal dominant disorders with overlapping phenotypic characteristics including hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features (Tartaglia and Gelb, 2005)
The top 250 genes based on ranked fold change values were extracted as NS and LS transcriptomic signatures
We proposed a hybrid strategy to integrate transcriptomic and structure approaches to look for respective repositioning candidates for NS and LS

Summary

Introduction

Noonan syndrome (NS) and LEOPARD syndrome [LS, called Noonan syndrome with multiple lentigines (NSML)] are autosomal dominant disorders with overlapping phenotypic characteristics including hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features (Tartaglia and Gelb, 2005). The exact prevalence of LS is unknown and approximately 200 cases have been reported globally The missense mutation in PTPN11 genes, resulting in a gain-of-function of the non-receptor protein tyrosine phosphatase SHP-2 protein causes approximately 50% of NS cases. Causative mutations in other genes (e.g., SOS1, RIT1, and KRAS) involved in RASMAPK pathways have been identified in a small portion of patients with NS (Schubbert et al, 2006; Pandit et al, 2007; Kouz et al, 2016). Mutations in PTPN11 causes approximately 70% of LS. The current management for LS and NS mainly relies on treating the phenotypic presentation of a specific organ or system based on the individual patient (Romano et al, 2010). No drugs have been approved for treating NS or LS by the U.S Food and Drug Administration (FDA)

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