Computational studies on potential small molecule inhibitors of pteridine reductase 1.

Leishmaniasis is a neglected tropical disease of major public health concern. Challenges with current therapeutics have led to the exploration of plant medicine for potential antileishmanial agents. Despite the promising activity of some antileishmanial natural products, their protein targets have not been explored. The relevance of folate metabolism in the parasite's existence presents crucial targets for the development of antileishmanial chemotherapy. Pteridine reductase 1 (PTR1), a crucial enzyme involved in DNA biosynthesis, is a validated target of the parasite. Unearthing inhibitors of this enzyme is therefore an active research area. The goal of this work is to unearth small molecule inhibitors of PTR1 using molecular docking and molecular dynamic simulations. Thus, the interactions between selected antileishmanial natural products and PTR1 were examined. The binding affinities obtained from molecular docking ranged from -6.2 to -9.8 kcal/mol. When compared to the natural PTR1 substrate biopterin, compounds such as anonaine, chimanine D, corynantheine, grifolin, licochalcone A, piperogalin and xylopine produced better binding affinities, making interactions catalytic residues - Tyr194, Asp181, Phe113, Arg17 and Ser111. The PTR1- xylopine, -piperogalin, -grifolin, and -licochalcone A complexes exhibited remarkable stability under dynamic conditions during the entire 200 ns simulation period. The overall binding free energy of grifolin, piperogalin, and licochalcone A were observed to be -105.711, -103.567, and -105.646 kJ/mol respectively. The binding of these complexes was observed to be favorable and spontaneous and as such capable of inhibiting Leishmania PTR1. They could therefore be considered as candidates in the development of antileishmanial chemotherapy.Communicated by Ramaswamy H. Sarma.