9B2E

DHNA associated with an inhibitor

Summary for 9B2E

• Entry DOI: 10.2210/pdb9b2e/pdb
• Descriptor: 7,8-dihydroneopterin aldolase, 2-amino-8-sulfanyl-1,9-dihydro-6H-purin-6-one (3 entities in total)
• Functional Keywords: protein complex, lyase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 27298.71

Authors

Czeczot, A.M.,Silva, E.E.D.,Timmers, L.F.S.M.,Machado, P.,Basso, L.A.,Bizarro, C.V. (deposition date: 2024-03-15, release date: 2025-02-19)

Primary citation

Czeczot, A.M.,Muniz, M.N.,Perello, M.A.,Silva, E.E.D.,Timmers, L.F.S.M.,Berger, A.,Gonzalez, L.C.,Arrache Goncalves, G.,Moura, S.,Machado, P.,Bizarro, C.V.,Basso, L.A.
Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.
J Enzyme Inhib Med Chem, 39:2388207-2388207, 2024

PubMed Abstract: The crystallographic structure of the FolB enzyme from (FolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of FolB. These compounds exhibited IC values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the H37Rv strain were evaluated. Compound exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting FolB, an attractive molecular target for TB drug development.

PubMed: 39140692
DOI: 10.1080/14756366.2024.2388207

Experimental method

X-RAY DIFFRACTION (1.95 Å)