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. Author manuscript; available in PMC: 2025 Mar 24.
Published in final edited form as: J Med Chem. 2025 Feb 7;68(4):4829–4847. doi: 10.1021/acs.jmedchem.4c03104

Figure 2. Binding of 37 to the DHI binding site in the Nurr1 LBD.

Figure 2

(a) Overview of the Nurr1 LBD (pdb ID 6dda19) with 37 (cyan) docked to the DHI binding site. (b) Predicted binding mode of 37. The chloroindole favorably occupies the DHI binding pocket behind helix 12 lined by Arg515, Arg563 and Cys566. The quinoline motif is bound in a rather hydrophobic surface pocket (Leu437) and the amide engages H-bonds to Ser441 and His516. (c) 37 exhibited slightly reduced potency and efficacy on C566S Nurr1 (EC50 0.11±0.02 μM, 1.7±0.1-fold act.) compared to the wildtype (wt; EC50 0.06±0.02 μM, 1.9±0.1-fold act.) suggesting importance of Cys566 for interaction but no covalent binding. Data are the mean±S.E.M., n≥4.