Spiro‐Acridine Compound as a Pteridine Reductase 1 Inhibitor: in silico Target Fishing and in vitro Studies

Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10 μg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1’s putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1 μM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1‐compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds. A series of spiro‐acridine derivatives have been identified with activity against Leishmania chagasi. However, their mechanism of action has not been elucidated. In this work, we used the computational target fishing method to identify the target and we identified the enzyme Pteridine reductase 1. The predicted target is supported by in vitro assays that confirm the conformation of the complex.