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Present work aims to utilize systems biology and molecular modelling approach to understand the inhibition kinetics of  Leishmania major  GLO I and identifying potential hit followed by their validation through  in vitro  and animal studies. Simulation of GLO I inhibition has shown to affect reaction fluxes of almost all reactions in the model that led to increased production of various AGEs and free radicals. Further,  in vitro  testing of C1 and C2, selected through molecular modelling revealed remarkable morphological alterations like size reduction, membrane blebbing and loss in motility of the parasite, however, only C1 showed better antileishmanial activity. Additionally, C1 showed apoptosis mediated leishmanicidal activity (apoptosis-like cell death) along with cell-cycle arrest at sub-G0/G1 phase and exhibited potent anti-leishmanial effect against intracellular amastigotes. Furthermore, decrease in parasite load was also observed in C1 treated BALB/c female mice. Our results indicate that C1 has healing effect in infected mice and effectively reduced the parasitic burden. Hence, we suggest C1 as a lead molecule which on further modification, may be used to develop novel therapeutics against  Leishmaniasis .

Multiscale Process Modelling in Translational Systems Biology of Leishmania major: A Holistic view