A tamoxifen receptor within a voltage-gated sodium channel.

Voltage-gated sodium channels are targets for many analgesic and antiepileptic drugs whose therapeutic mechanisms and binding sites have been well characterized. We describe the identification of a previously unidentified receptor site within the NavMs voltage-gated sodium channel. Tamoxifen, an estrogen receptor modulator, and its primary and secondary metabolic products bind at the intracellular exit of the channel, which is a site that is distinct from other previously characterized sodium channel drug sites. These compounds inhibit NavMs and human sodium channels with similar potencies and prevent sodium conductance by delaying channel recovery from the inactivated state. This study therefore not only describes the structure and pharmacology of a site that could be leveraged for the development of new drugs for the treatment of sodium channelopathies but may also have important implications for off-target health effects of this widely used therapeutic drug.

Targeting novel sites in DNA gyrase for development of anti-microbials.

Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in the appearance of multiple drug resistance in bacterial pathogens and a decline in the discovery of novel antibiotics. DNA gyrase is an attractive target used for antibiotic discovery due to its vital role in bacterial DNA replication and segregation in addition to its absence in mammalian organisms. Despite the presence of successful antibiotics targeting this enzyme, there is a need to bypass the resistance against this validated drug target. Hence, drug development in DNA gyrase is a highly active research area. In addition to the conventional binding sites for the novobiocin and fluoroquinolone antibiotics, several novel sites are being exploited for drug discovery. The binding sites for novel bacterial type II topoisomerase inhibitor (NBTI), simocyclinone, YacG, Thiophene and CcdB are structurally and biochemically validated active sites, which inhibit the supercoiling activity of topoisomerases. The novel chemical moieties with varied scaffolds have been identified to target DNA gyrase. Amongst them, the NBTI constitutes the most advanced DNA gyrase inhibitor which are in phase III trial of drug development. The present review aims to classify the novel binding sites other than the conventional novobiocin and quinolone binding pocket to bypass the resistance due to mutations in the DNA gyrase enzyme. These sites can be exploited for the identification of new scaffolds for the development of novel antibacterial compounds.

Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer.

While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human colon cancer cells with an IC50 of 0.8 µM in SW480 cells and inhibited xenotransplanted tumor growth in a dose-dependent manner. Using affinity chromatography, we identified sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 as the binding target of RL71. Most notably, RL71 demonstrated special binding to SERCA2 at a novel site with the lowest estimated free energy -8.89 kcal mol(-1), and the SERCA2 residues critical for RL71 binding were identified. RL71 suppressed the Ca(2+)-ATPase activity of SERCA2 both in vitro and in vivo, accompanied by the induction of endoplasmic reticulum stress leading to apoptosis and G2/M cycle arrest in SW480 cells. In addition, RL71 showed synergistic cytotoxicity with the pan-SERCA inhibitor thapsigargin. These results suggest that RL71 could be a selective small-molecule inhibitor of SERCA2, and that it may serve as a lead compound for the study of targeted colorectal cancer therapy.