Beyond traditional medications: exploring novel and potential inhibitors of trypanothione reductase (LmTr) of Leishmania parasites

• Published in: Journal of biomolecular structure & dynamics pp. 1 - 14
• Main Authors: Sarfraz, Muhammad, Bakht, M Afroz, Alshammari, Mohammed Sanad, Alrofaidi, Mohammad, Alzahrani, Abdullah R, Eltaib, Lina, Asdaq, Syed Mohammed Basheeruddin, Aba Alkhayl, Faris F, Abida, Mohd Imran
• Format: Journal Article
• Language: English
• Published: England 04.01.2024
• Subjects: inhibitors; hit-to-lead approach; leishmania major; virtual screening; trypanothione reductase; Leishmaniasis; evasion strategies
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2300062

The trypanothione reductase enzyme, which neutralizes the reactive oxygen species produced inside the macrophages to kill the parasites, is one of the evasion strategies Leishmania uses to survive inside the cells. The vitality of the parasite depends on trypanothione reductase (LmTr), a NADPH-dependent flavoprotein oxidoreductase essential for thiol metabolism. Since this enzyme is distinct and lacking in humans, we focused on it in our study to screen for new inhibitors to combat leishmaniasis. Using the I-TASSER server, a three-dimensional model of LmTr was generated. The Autodock vina program was used in high-throughput virtual screening of the ZINC database. The top seven molecules were ranked according to their binding affinity. The compounds with the highest binding affinities and the right number of hydrogen bonds were chosen. These compounds may be effective at inhibiting the target enzyme's (LmTr) activity, making them new leishmaniasis treatments. These compounds may serve as a useful starting point for a hit-to-lead approach in the quest for new anti-Leishmania drugs that are more efficient and less cytotoxic. The average node degree is 5.09, the average local clustering coefficient is 0.868, and the PPI enrichment p-value is 8.9e-06, indicating that it is sufficiently connected to regulate the network. TRYR (LmTr protein) also interacts physically with ten additional proteins in the pathogenesis network. The findings of the study indicated that successfully suppressing the LmTr protein and may finally result in regulating the L. major pathogenesis.Communicated by Ramaswamy H. Sarma.