Integrated computational and experimental approach for novel anti-leishmanial molecules by targeting...

Coenzyme A acts as a necessary cofactor for many enzymes and is a part of many biochemical processes. One of the critical enzymes involved in Coenzyme A synthesis is Dephospho-coenzyme A-kinase (DPCK). In this study, we have used integrated computational and experimental approaches for promising inhibitors of DPCK using the natural products available in the ZINC database for anti-leishmanial drug development. The top hit compounds chosen after molecular docking were Veratramine, Azulene, Hupehenine, and Hederagenin. The free binding energy of Veratramine, Azulene, Hupehenine, and Hederagenin was estimated. Besides the favourable binding point, the ligands also showed good hydrogen bonding and other interactions with key residues of the enzyme's active site. The natural compounds were also experimentally investigated for their effect on the L. donovani promastigotes and murine macrophage (J774A.1). A good antileishmanial activity by the compounds on the promastigotes was observed as estimated by the MTT assay. The in-vitro experiments revealed that Hupehenine (IC₅₀ = 7.34 ± 0.37 μM) and Veratramine (IC₅₀ = 12.46 ± 2.28 μM) exhibited better inhibition than Hederagenin (IC₅₀ = 23.36 ± 0.54 μM) and Azulene (IC₅₀ = 24.42 ± 3.28 μM). This work has identified novel anti-leishmanial molecules possibly acting through the inhibition of DPCK.