Targeting metabolic pathways proteins of Orientia tsutsugamushi using combined hierarchical approach to combat scrub typhus

• Published in: Journal of molecular recognition Vol. 32; no. 4; pp. e2766 - n/a
• Main Authors: Sharma, Dixit, Sharma, Ankita, Verma, Shailender Kumar, Singh, Birbal
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2019
• Subjects: Bacterial Outer Membrane Proteins - metabolism; Binding; Catalysis; Chemical compounds; Computer applications; Computer simulation; Deoxyribonucleic acid; DNA; Docking; Dynamic stability; Homology; Medical treatment; Membrane proteins; Membrane Proteins - metabolism; Metabolic Networks and Pathways - physiology; Metabolic pathways; Metabolism; molecular docking; Molecular dynamics; Organic chemistry; Orientia tsutsugamushi; Orientia tsutsugamushi - metabolism; Outer membrane proteins; Pathogenesis; Pathogens; Proteins; Reproducibility of Results; Scrub typhus; Therapeutic applications; therapeutic targets; Typhus; unique pathways; Zoonoses; molecular docking; therapeutic targets; unique pathways; Orientia tsutsugamushi; scrub typhus
• ISSN: 0952-3499; 1099-1352
• DOI: 10.1002/jmr.2766

Orientia tsutsugamushi (Ott) is a causative agent of chigger‐borne zoonosis, scrub typhus which is life threatening and highly pervasive illness in humans. In this report, we have mined and classified the proteins involved in pathways unique to Ott by using high‐throughput computational techniques. The 12 metabolic pathways were found to be unique to the pathogen. Forty‐six proteins were reported to be essential for the pathogen's survival and non‐homologous to the humans. The proteins were categorized into different classes, ie, enzymes, transporters, DNA‐binding, secretory, and outer membrane proteins. Further, in silico analysis of 46 proteins showed that 25 proteins were suitable therapeutic targets with known druggable properties. The structural modeling of B3CSG3 (MurA) protein was carried out and catalytic site essential for its functioning was analyzed. Virtual screening of chemical compounds was performed against modeled structure. The docking study by AutodockVina reported compound from PubChem with CID: 16036947 as best and potential inhibitor by means of docking score and binding affinity. The reliability and stability of the MurA‐16036947 complex were confirmed with molecular dynamics simulation. The report will provide insight to understand the mechanism of pathogenesis of Ott and instigate the development of effective treatment strategies against this disease. Metabolic pathways proteins of Orientia tsutsugamushi are elite and have the potential to serve as therapeutic targets. Twelve metabolic pathways were found unique to the pathogen and 46 proteins involved in these pathways were essential to pathogen's survival and non‐homologous to humans. Novel inhibitor (PubChem CID: 16036947) of MurA was reported which have the efficiency for future effective drug development against scrub typhus.