Extended Data Fig. 5: Analysis of CypD-selective prolyl isomerase inhibition based on S2 pocket containing residues.
From: Discovery and molecular basis of subtype-selective cyclophilin inhibitors
IC50 values for each cyclophilin are accompanied by fold difference normalized to \({\mathrm{IC}}^{\mathrm{CypD}}_{50}\). Residues listed next to each cyclophilin are the important proximal residues near the carboxylate-containing ligands. CsA does not bind the S2 pocket and shows almost no cyclophilin isoform selectivity, while B2’s large biphenyl group exhibits selectivity over cyclophilins with sterically occluded S2 pockets. Further selectivity over CypC, Cyp40, and PPIL1 is achieved through interactions between CypD’s K118 residue and carboxylate-containing ligands such as B23. Installation of dicarboxylates in B52 and B53 result in CypD selectivity by presenting a second carboxylate near the analogous S123 position on CypD. Potency for CsA, B2, and B23 values reflect mean of three technical replicates. Potency for B52 and B53 values reflect mean of four independent replicates.
