Identification of MAPK3 inhibitors against Leishmania spp. via in silico and in vitro approaches

Abstract

Importance: Leishmaniasis, caused by Leishmania parasites, is a significant global health issue with limited treatment options. Mitogen-activated protein kinase 3 (MAPK3) plays a crucial role in parasite survival and immune evasion, making it a promising therapeutic target. Nevertheless, existing treatments have substantial side effects, and no specific MAPK3 inhibitors are available. Objective: This study evaluated the potential MAPK3 inhibitors capable of targeting L. donovani and L. martiniquensis using computational and experimental approaches. Methods: Five compounds from the NCI database were screened using an ADP-Glo Kinase Assay for MAPK3 inhibition. Half-maximal inhibitory concentration (IC<inf>50</inf>) analysis was performed to determine their potency. Molecular docking and molecular dynamics simulations were conducted to assess the binding interactions and stability. Cell-based assays were performed to evaluate the efficacy of these compounds against L. donovani and L. martiniquensis in the promastigote and amastigote stages. Results: NSC107522, NSC196515, and NSC84100 inhibited MAPK3, with IC<inf>50</inf> values of 2.69 µM, 4.96 µM, and 10.59 µM, respectively. NSC107522 showed the strongest binding affinity (ΔG<inf>bind</inf> = −111.20 kJ/mol) and reduced L. donovani survival in the promastigote (IC<inf>50</inf> = 2.68 µM) and amastigote (IC<inf>50</inf> = 4.04 µM) stages. NSC84100 exhibited superior activity against L. martiniquensis, with IC<inf>50</inf> values of 3.14 µM (promastigotes) and 2.61 µM (amastigotes). Conclusions and Relevance: NSC107522 and NSC84100 are promising MAPK3 inhibitors with species-specific activity. NSC107522 targets L. donovani, while NSC84100 is more effective against L. martiniquensis. These findings provide a foundation for developing targeted therapies against leishmaniasis, but further studies will be needed to determine their in vivo efficacy and optimize MAPK3-targeted drug design.