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. 2018 Jul 19;128(10):4485–4500. doi: 10.1172/JCI99768

Figure 1. Structure-based drug design of compound 3, GS-444217.

Figure 1

(A) Medicinal chemistry optimization of compound 1 showing improved biochemical potency (IC50) and maintenance of low lipophilicity resulting in improved lipophilic ligand efficiency (LLE). (B) Structure of compound 1 occupying the ATP-binding pocket of ASK1. Interactions between hinge residue Val757 and the catalytic residue Lys709 are highlighted. (C) Structure of compound 2 bound to ASK1 with a cross-dimer interaction to the Tyr814 residue of the neighboring ASK1 monomer. (D) Structure of compound 3 (GS-444217) bound to ASK1.