System biology approach for functional annotation of the genome of human malaria parasite plasmodium falciparum and antimalarial drug discovery

• Main Author: Naw, Wah Wah
• Other Authors: Zbynek Bozdech
• Format: Theses and Dissertations
• Language: English
• Published: 2015
• Subjects: DRNTU::Science::Biological sciences
• Online Access: http://hdl.handle.net/10356/65593
• Institution: Nanyang Technological University

In this study, a gene co-expression network with a special focus on the P. falciparum exportome is constructed to annotate hypothetical proteins in P. falciparum. The project includes three sections: 1) transcriptional profiling of growth perturbations using 400 compounds in Malaria Box provided by Medicine for Malaria Venture, 2)construction of gene co-expression network and functional annotation of hypothetical proteins and 3) functional characterization of 3 parasite exported proteins and 3 mitochondrial proteins to validate the predicted functions. In addition, the potential utility of the transcriptional data set for mode of action (MOA) discovery for 400 compounds has been explored to speed up antimalarial drug discovery. A compendium of 400 transcriptional profiles would be offered to malaria research community through PlasmoDB (http://plasmodb.org/plasmo/). The gene coexpression network obtained in this study allows us to predict the function of 525 genes in the genome of P. falciparum. MMV compounds were clustered into 23 clusters and a singleton based on transcriptional similarity. Pathways that are significantly up regulated include pathways related to transcription, protein synthesis, oxidative stress response and virulence. Pathways that are significantly down regulated include pathways related to DNA replication, invasion and environmental stress response. 81 Compounds were discovered to share structural similarity with clinical drugs. The mode of action and protein targets of these drugs allow us to generate hypotheses on the MOAs of these antimalarial compounds.