5A54

DYRK1A IN COMPLEX WITH NITRO BENZOTHIAZOLE FRAGMENT

Summary for 5A54

• Entry DOI: 10.2210/pdb5a54/pdb
• Related: 5A4L 5A4Q 5A4T
• Descriptor: DUAL SPECIFICITY TYROSINE-PHOSPHORYLATION-REGULATED KINASE 1A, N-(6-nitro-1,3-benzothiazol-2-yl)ethanamide (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 4
• Total formula weight: 171564.91

Authors

Rothweiler, U. (deposition date: 2015-06-16, release date: 2016-06-29, Last modification date: 2024-10-09)

Primary citation

Rothweiler, U.,Stensen, W.,Brandsdal, B.O.,Isaksson, J.,Leeson, F.A.,Eugh, R.A.,Mjoen Svendsen, J.S.
Probing the ATP-Binding Pocket of Protein Kinase Dyrk1A with Benzothiazole Fragment Molecules
J.Med.Chem., 59:9814-, 2016

PubMed Abstract: DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.

PubMed: 27736065
DOI: 10.1021/ACS.JMEDCHEM.6B01086

Experimental method

X-RAY DIFFRACTION (2.63 Å)