Flavones reversibly inhibit Leishmania donovani tyrosine aminotransferase by binding to the catalytic pocket: An integrated in silico-in vitro approach.

The current drugs for treating Leishmaniasis are toxic, non-economical and with the emergence of drug resistance makes the need for novel therapeutics urgent and necessary. In the current study, we report the identification of compounds TI 1-5 against tyrosine aminotransferase of L. donovani from a curated ZINC15 database containing 183,659 compounds. These flavonoid compounds had binding energies < -8 kcal/mol and interacted with the active site residues S151, K286, C290, and P291. Assessment of physicochemical descriptors and ADMET properties established the drug likeliness of these compounds. The all-atom molecular dynamic simulations of the TAT-TI complexes exhibited stable geometrical properties and further trajectory analysis revealed the high-affinity interactions of TI 1, 3, 4, and 5 with the active site residues. DFT calculations reported the high electrophilic nature of TI 2 while other TI compounds demonstrated good kinetic stability and reactivity. From in vitro studies, TI 3 and TI 4 had the highest inhibition with Ki values of 0.9 ± 0.2 μM and 0.30 ± 0.1 μM, respectively. Taken together, the results from this study indicate the potentiality of TI 1, 3, 4, and 5 as anti-leishmanial leads, and these compounds can be exploited to manage the growing Leishmaniasis crisis in the world.