Extended Data Fig. 6: Inhibition potency is dependent on favorable interactions with S2 pocket residues.
From: Discovery and molecular basis of subtype-selective cyclophilin inhibitors
Dose response curves for B52 against a, CypB E121S mutant and b, CypA E81S/K82R double mutant, with residue tables for important dicarboxylate proximal residues. Mutated residues are underlined. B52 inhibits both CypB and CypA mutants that have the appropriate ‘CypD’ gatekeeper residues at similar potency values compared to wild-type CypD. c, Dose response curves for B32 against wild-type CypD and CypD mutants shown in the table. Two mutations to remove positively charged residues K118 and R124 restore inhibition potency of amine derivative B32. d, Structure of B32. For CypD, CypA, and CypB wild-type IC50 data with B52, values reflect mean ± s.d. of four independent replicates (each comprising three technical replicates). Graphs show a representative single independent replicate (Independent replicate 1 is shown, containing three technical replicates) with data points and error bars reflecting mean ± s.d. of individual assays at one dose. Further independent replicates are shown in Supplementary Fig. 18b-c. All other IC50 values reflect mean ± s.e.m. of three technical replicates, with data points and error bars reflecting mean ± s.d. of individual assays at one dose.
