**4. Conclusion**

Trypanothione reductase has been a well-investigated target essential for trypanosomatids. Its function in controlling oxidative stress in the parasite provided an opportunity to target the trypanothione biosynthesis pathway. A total of 11 hit compounds identified by pharmacophore modeling and virtual screening were filtered to four potential leads by considering their ADME with their molecular interactions in *Lm*TR. MM-PBSA enabled the individual computation of active site residues that contributed significantly to binding. Efficient selective blockade of *Lm*TR with these four coumarin compounds: Karatavicinol (7-[(2E,6E,10S)-10,11 dihydroxy-3,7,11-trimethyldodeca-2,6-dienoxy]chromen-2-one), Marmin (7- [(E,6R)-6,7-dihydroxy-3,7-dimethyloct-2-enoxy]chromen-2-one), Pectachol (7- [(6-hydroxy-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1*H*naphthalen-1-yl)methoxy]-6,8-dimethoxychromen-2-one), and Colladonin (7- [[(4*aS*)-6-hydroxy-5,5,8*a*-trimethyl-2-methylidene-3,4,4*a*,6,7,8-hexahydro-1*H*naphthalen-1-yl]methoxy]chromen-2-one) hold the potential to compromise the redox defenses of the parasites by inhibiting the FAD binding region and correspondingly increasing their sensitivity to redox-damage when carried out in *in vitro* and *in vivo* studies. Residues such as Asp35, Thr51, Lys61, Tyr198, and Asp327 are suspected to have critical role in the anchoring of FAD which contributes to the formation of reduced T[SH]2 in the reducing environment of amastigotes.

#### **Acknowledgements**

The authors are grateful to the West African Centre for Cell Biology of Infectious Pathogens (WACCBIP) at the University of Ghana for making Zuputo, a Dell EMC high-performance computing cluster, available for this study.
