Identification of a novel ligand binding motif in the transthyretin channel

Inhibition of Human Transthyretin Aggregation by Non-Steroidal Anti-Inflammatory Compounds: A Structural and Thermodynamic Analysis

“…Taking into account the functional data obtained from the binding, stabilization and aggregation assays, it is suggestive that either more contacts with the HBP and binding involving less insertion into the channel might result in better TTR affinity and privileged effectiveness in preventing dissociation and aggregation. However, the present data also support the notion that TTR is still a particularly challenging case for rational drug design, because ligand binding and orientation inside the channel are not highly predictive based on previous data using homologous series; this was observed for the two distinctive orientations—forward and reverse—between diclofenac and lumiracoxib and the rotational orientation inside the channel as supported by crystallographic data with diclofenac [43] and the two analogs SUL and IND.…”

“…Moreover, hydration of this cavity did not seem to be costly, as suggested by the existence of a water molecule in a partially occupied region in the apo form of TTR. Collectively, the intrinsic dynamics of Lys15 and Leu17 and the inductive characteristic of this cavity, as suggested by the recent identification of this site [43], reinforced the possible use of these features in the optimization of lead compounds targeting TTR.…”

“…Initially, we measured the affinity of LUM, IND and SUL for WT-TTR and L55P using ANS displacement from the HBS [43]. As shown in Figure S1 and Table S1, all compounds displayed apparent dissociation constants in the range between 1 and 7 μM, and LUM had the highest affinities for WT-TTR and L55P (1.4 and 1.7 μM, respectively).…”

“…Diclofenac has long been investigated as a model for the design of analogues targeting TTR [42,43]. Both diclofenac and diclofenac analogues bind to TTR in the so-called “reverse mode”, i.e.…”

“…, with the phenylacetic moiety occupying the inner binding cavity [42]. We have recently shown that diclofenac binds to TTR in at least two alternate modes, with the dihalogen-substituted ring rotated at about 90 degrees taking the phenylacetic moiety as a positional reference [43]. In contrast to diclofenac, LUM bound to TTR in the “forward mode”, i.e.…”