In silico Metabolic Pathway Analysis Identifying Target Against Leishmaniasis – A Kinetic Modeling Approach

The protozoan Leishmania donovani, from trypanosomatids family is a deadly human pathogen responsible for causing Visceral Leishmaniasis. Unavailability of proper treatment in the developing countries has served as a major threat to the people. The absence of vaccines has made treatment possibilities to rely solely over chemotherapy. Also, reduced drug efficacy due to emerging resistant strains magnifies the threat. Despite years of formulations for an effective drug therapy, complexity of the disease is also unfortunately increasing. Absence of potential drug targets has worsened the scenario. Therefore exploring new therapeutic approach is a priority for the scientific community to combat the disease. One of the most reliable ways to alter the adversities of the infection is finding new biological targets for designing potential drugs. An era of computational biology allows identifying targets, assisting experimental studies. It includes sorting the parasite's metabolic pathways that pins out proteins essential for its survival. We have directed our study towards a computational methodology for determining targets against L. donovani from the "purine salvage" pathway. This is a mainstay pathway towards the maintenance of purine amounts in the parasitic pool of nutrients proving to be mandatory for its survival. This study represents an integration of metabolic pathway and Protein-Protein Interactions analysis. It consists of incorporating the available experimental data to the theoretical methods with a prospective to develop a kinetic model of Purine salvage pathway. Simulation data revealed the time course mechanism of the enzymes involved in the synthesis of the metabolites. Modeling of the metabolic pathway helped in marking of crucial enzymes. Additionally, the PPI analysis of the pathway assisted in building a static interaction network for the proteins. Topological analysis of the PPI network through centrality measures (MCC and Closeness) detected targets found common with Dynamic Modeling. Therefore our analysis reveals the enzymes ADSL (Adenylosuccinate lyase) and IMPDH (Inosine-5'-monophosphate dehydrogenase) to be important having a central role in the modeled network based on PPI and kinetic modeling techniques. Further the available three dimensional structure of the enzyme "ADSL" aided towards the search for potential inhibitors against the protein. Hence, the study presented the significance of integrating methods to identify key proteins which might be putative targets against the treatment of Visceral Leishmaniasis and their potential inhibitors.