Discovery of 8-hydroxy-2-quinoline carbaldehyde derivatives as inhibitors for M1 aminopeptidase of Leishmania donovani.

Autor: Kumar J; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Prof. C.R. Rao Road, Hyderabad 500046, India., Jyotisha; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Prof. C.R. Rao Road, Hyderabad 500046, India., Qureshi R; Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India., Jagruthi P; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India., Arifuddin M; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India., Qureshi IA; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Prof. C.R. Rao Road, Hyderabad 500046, India. Electronic address: insaf@uohyd.ac.in.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Nov; Vol. 279 (Pt 2), pp. 135105. Date of Electronic Publication: 2024 Aug 26.
DOI: 10.1016/j.ijbiomac.2024.135105
Abstrakt: M1 aminopeptidase is a metallopeptidase that plays a vital role in protein catabolism and has been identified as a validated drug target in various parasites; however, our understanding of this enzyme is restricted for leishmanial parasite. The present investigation involved the purification of Leishmania donovani M1 aminopeptidase (LdM1AP) to homogeneity by affinity chromatography. Purified LdM1AP was observed to be enzymatically active and displayed maximal activity in the presence of cobalt ions, whereas secondary structure analysis confirmed the dominance of α-helices. Intrinsic fluorescence and quenching studies of LdM1AP has revealed that tryptophan residues were predominantly concealed within the hydrophobic areas. The synthesized 8-hydroxy-2-quinoline carbaldehyde derivatives were screened, wherein HQ2 and HQ12 were found as potent inhibitors for LdM1AP that compete with the substrate and exhibit pharmacokinetic properties as well as no toxicity for macrophages. Moreover, structural insights of protein and ligand complexes demonstrated that lead compounds mostly interact via hydrophobic contacts into the substrate binding pocket of LdM1AP. Furthermore, lead compounds exhibited a greater affinity for LdM1AP compared to the substrate during in vitro and in silico studies. This report establishes the possibility of quinoline derivatives to target the LdM1AP activity and provide a platform to design the specific antileishmanial drugs.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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