Systems Biology Study of Yeast Mitogen Activated Protein Kinase (MAPK) Cascade for Novel Drug Target Identification against Fungal Pathogens

Abstract

Abstract-Novel drug target identification and drug discovery are potential fields of systems biology which is recently being implemented against various pathogens based on differential biological processes of host and pathogen. Due to closer extent of biological similarity of eukaryotic fungal pathogens with their hosts, it has been urgent to find out novel drug targets against fungal pathogens. It is seen that mitogen activated protein kinase (MAPK) cascade transmits signals from outer cell surface to the nucleus and is involved in fungal survival mechanisms against environmental stress conditions. MAPK cascade molecules can be good targets of antifungal drugs to avoid fungal survival against conventional drugs. From these perspectives, systems biology approaches have been undertaken with an aim to assess the MAPK molecules as antifungal drug targets to find out the best one using Yeast (Saccharomyces cerevisiae) as model organism, Human as host and Candida albicans as pathogen. Comparative proteomic study, protein-protein interaction study, sequence and structural analysis study, molecular docking study and mathematical modeling study have been conducted in this regard. A combined prioritizing scoring system has been used to identify the most optimal MAPK target based on weighted decision matrix and combined matrix position score (CMPS), stability of the matrix position score (SD) and total score (TS) have been introduced. MAPKs having TS less than the average TS (72.55) were screened out as better MAPK targets. The approach predicts SLT2/MPK1 among the 11 MAPK molecules the best target of antifungal drugs having the low est TS (54.49).Index Terms-Antifungal drug, MAPK cascade, novel drug target, signal transduction pathway, systems biology.

Macelignan inhibits bee pathogenic fungi Ascophaera apis growth through HOG1 pathway

“…In the present study, macelignan had antifungal activity only against C. neoformans, other than A. apis , which might infer the inhibition of MPK1 and/or HOG pathways. Recently, a systems biology study confirmed MPK1 among 11 MAPK molecules as the best target for antifungal drugs ( 39 ). Therefore, inhibition of A. apis and C. neoformans growth by macelignan treatment can be assumed through regulation of MPK1 and/or HOG1 pathways.…”