Molecular insights into how SHBG dimerization exerts changes on ligand molecular recognition.

Sex hormone binding globulin (SHBG) is a homodimeric glycoprotein and is the major carrier protein for sex steroids in plasma, regulating sex hormone availability in most vertebrate groups. Although it was initially thought that human dimeric SHBG bound a single ligand at the homodimer interface, studies demonstrated that dimeric SHBG binds a ligand to each subunit with similar affinity. In fact, the findings from recent experimental studies suggest that ligand binding to the SHBG dimer involves a complex allosteric mechanism involving conformational changes that limit observations of the presence of allosteric regulation. Therefore, we combined structural data with molecular dynamics simulations using Molecular Mechanics Generalized-Born Surface Area (MMGBSA) to dissect the structural and energetic basis for molecular recognition between five ligands whose affinities and binding positions on SHBG are known, i.e., 3ß,17α-diol; 3ß,17ß-diol; DHT; norgestrel (NOG); and estradiol (E2), and monomeric and dimeric SHBG. Protein-ligand complexes, involving dimeric SHBG saturated with two ligands on each subunit, reproduce the experimental affinity tendency and allow the observation that dimerization exerts disparate effects on binding affinity, characteristic of negative cooperativity for E2, DHT, and NOG, whereas 3ß-17α-diol and 3ß-17ß-diol lack allostery.

Dissecting the molecular recognition of dual lapatinib derivatives for EGFR/HER2.

Abnormalities in the expression levels of EGFR/HER2 are found in many different types of human cancer; therefore, the design of dual inhibitors of EGFR/HER2 is a recognized anti-cancer strategy. Some lapatinib derivatives have been previously synthesized by modification at the methylsulfonylethylaminomethylfuryl group and biologically evaluated, demonstrating that the 2i compound shows potent inhibitory activity against EGFR/HER2-overexpressing cancer cells. In the present study, we explored the structural and energetic features that guide the molecular recognition of 2i using various EGFR/HER2 states. Molecular dynamics (MD) simulation with an MMPB(GB)SA approach was used to generate the inactive EGFR/HER2-ligand complexes. Our results corroborate that slight modification of lapatinib contributes to an increase in the affinity of the 2i compound for inactive EGFR/HER2 as compared with lapatinib compound, which is in accordance with experimental results. Comparison with previous results reveals that lapatinib and its derivative bind more strongly to the inactive than the intermediate active-inactive HER2 state. Principal component analysis allowed the observation that coupling of 2i to EGFR/HER2 is linked to a reduction in the conformational mobility, which may also contribute to the improvement in affinity observed for this compound as compared with lapatinib.

Several effects of boron are induced by uncoupling steroid hormones from their transporters in blood.

Boron is increasingly added to food supplements due to multiple effects that have been reported in mammals after boric acid administration. Among these effects are inflammatory process control, bone and muscle strength enhancement, protein expression regulation, and a decreased risk of developing some pathologies in which these processes are key, such as osteoporosis, dermatological inflammatory non-infectious maladies and diseases affecting the central nervous system. Experimental data have suggested that steroid hormone levels in plasma change after boric acid administration, but a clear mechanism behind these variations has not been established. We analyzed possibilities for these changes and hypothesized that boric acid disrupts the interactions between steroid hormones and several carriers in plasma. In particular, we proposed that there is an uncoupling of the interactions between sex hormone binding globulin (SHBG) and estrogens and testosterone and that there are alterations in the binding of hydrophobic ligands by other carrier proteins in plasma. Further experimental and computational studies are required to support the hypothesis that boric acid and probably other boron-containing compounds can displace steroid hormones from their plasma carriers. If such phenomena are confirmed, boron administration with a clear mechanism could be employed as a therapeutic agent in several diseases or physiological events that require modulation of steroid hormone levels in plasma.