6m0t

Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum complexed with L-lysine and Cladosporin derivative (CL-2)

spinqualitylabelsall models 6m0t, resolution 2.68Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.68Å Ligands: EZ3, LYS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold. Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites.,Babbar P, Das P, Manickam Y, Mankad Y, Yadav S, Parvez S, Sharma A, Reddy DS ACS Infect Dis. 2021 Apr 12. doi: 10.1021/acsinfecdis.1c00092. PMID:33843204 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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