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

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 a...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research