Targeting Different Transthyretin Binding Sites with Unusual Natural Compounds

Misfolding and aggregation of the transthyretin (TTR) protein leads to certain forms of amyloidosis. Some nutraceuticals, such as flavonoids and natural polyphenols, have recently been investigated as modulators of the self-assembly process of TTR, but they generally suffer from limited bioavailability. To discover innovative and more bioavailable natural compounds able to inhibit TTR amyloid formation, a docking study was performed using the crystallographic structure of TTR. This computational strategy was projected as an adhoc inspection of the possible relationship between binding site location and modulation of the assembly process; interactions with the as-yet-unexplored epigallocatechin gallate (EGCG) sites and with the thyroxine (T4) pocket were simultaneously analyzed. All the compounds studied seem to prefer the traditional T4 binding site, but some interesting results emerged from the screening of an in-house database, used for validating the computational protocol, and of the Herbal Ingredients Targets (HIT) catalogue available on the ZINC database

Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands

Estrogens play a crucial role in the development and function of female reproductive tissues. They have positive effects on the maintenance of bone mineral density, on the liver, and on the cardiovascular and central nervous systems. Selective Estrogen Receptor Modulators (SERMs) are particularly attractive as therapeutic agents because they are able to block estrogen action at those sites where stimulation would be undesirable, such as the breast and uterus, but at the same time stimulate estrogen actions in other tissues where they are desired, such as the bone and liver. Most synthetic estrogen receptor ligands possess a phenolic ring, mimicking the phenolic "Aring" of the natural ligand estradiol. In an attempt to increase the structural diversity of estrogen receptor (ER) ligands, we designed and synthesized molecules containing unprecedented replacements of the prototypical phenolic "A-ring" of estrogens with an oxime and a hydroxy- (salicylaldoximes) or aminomoieties (anthranylaldoximes), forming intramolecularly H-bonded pseudocycles. These new classes of compounds showed interesting ER binding properties on both receptor subtypes (ERα and ERβ). These results proved that the six-membered ring formed by an intramolecular hydrogen bond, and containing an exocyclic oxime OH, is an effective stereoelectronic replacement of the phenolic ring of typical ER ligands

Computational Studies on Transthyretin

Among the 23 different fibril proteins described in human amyloidosis, transthyretin is associated with the most common hereditary form of the disease and its knowledge is corroborated through about 150 crystal structures in addition to thousands of small ligands tested as fibril formation inhibitors. In spite of the large amount of available data, the mechanism of transthyretin aggregation and its inhibition through binding with small ligands is not clear. In the last decade, many groups of researchers have attempted to apply computational procedures to simulate these phenomena, with the aim of understanding them in depth and in order to rationalize the design of new promising inhibitors. A summary of the main molecular dynamics, docking, and structure-activity relationship studies carried out on transthyretin are reviewed here, and the most successful results and new trends are described in detail

Different Binding Modes of Structurally Diverse Ligands for Human D3DAR

Five different dopamine D3 receptors (D3DARs) models were created considering some suggested binding modes for D3DAR antagonists reported in earlier computational studies. Different hypotheses are justified because of the lack of experimental information about the putative site of interaction and are also due to the variability in scaffolds and size of D3DAR ligands. In this study 114 potent and selective D3DAR antagonists or partial agonists are used as key experimental information to discriminate the most reliable receptor model and to build a docking based 3D quantitative structure-activity relationship model able to indicate the ligand properties and the residues important for activity. The ability of this D3DAR model to discriminate the binding mode of different classes of ligands, showing a good quantitative correlation with their activity, encourages us to use it for screening novel lead compounds

Development of a receptor-based 3D-QSAR study for the analysis of MMP2, MMP3, and MMP9 inhibitors

The ability of Gold software to predict the binding disposition of matrix metalloproteinase (MMP) inhibitors was evaluated using MMP3 and MMP8. The best procedure was subsequently employed to dock into MMP2, MMP3 and MMP9 nearly 70 compounds that were tested for their inhibitory activity against the three MMP subtypes. The best binding poses were used as an alignment tool for the development of 3D-QSAR studies. Evaluation of the three resulting 3D-QSAR models allowed us to indicate the ligand properties and residues important for activity and selectivity. MMP2 is an important anticancer drug target, while MMP3 and MMP9 are considered to be anti-targets for tumor pathologies. As such, our results could predict the binding affinities of new MMP2 inhibitors, providing additional information regarding the selectivity against MMP3 and MMP9. Furthermore, this strategy may be used also for the investigation of other MMPs