Predicting Where Small Molecules Bind at Protein-Protein Interfaces.

Predicting where Small Molecules Bind at Protein-Protein Interfaces.

PLoS One. 2013; 8(3): e58583
Walter P, Metzger J, Thiel C, Helms V

Small molecules that bind at protein-protein interfaces may either block or stabilize protein-protein interactions in cells. Thus, some of these binding interfaces may turn into prospective targets for drug design. Here, we collected 175 pairs of protein-protein (PP) complexes and protein-ligand (PL) complexes with known three-dimensional structures for which (1) one protein from the PP complex shares at least 40% sequence identity with the protein from the PL complex, and (2) the interface regions of these proteins overlap at least partially with each other. We found that those residues of the interfaces that may bind the other protein as well as the small molecule are evolutionary more conserved on average, have a higher tendency of being located in pockets and expose a smaller fraction of their surface area to the solvent than the remaining protein-protein interface region. Based on these findings we derived a statistical classifier that predicts patches at binding interfaces that have a higher tendency to bind small molecules. We applied this new prediction method to more than 10 000 interfaces from the protein data bank. For several complexes related to apoptosis the predicted binding patches were in direct contact to co-crystallized small molecules. HubMed – drug


Use of Population-based Surveillance to Define the High Incidence of Shigellosis in an Urban Slum in Nairobi, Kenya.

PLoS One. 2013; 8(3): e58437
Njuguna HN, Cosmas L, Williamson J, Nyachieo D, Olack B, Ochieng JB, Wamola N, Oundo JO, Feikin DR, Mintz ED, Breiman RF

Worldwide, Shigella causes an estimated 160 million infections and >1 million deaths annually. However, limited incidence data are available from African urban slums. We investigated the epidemiology of shigellosis and drug susceptibility patterns within a densely populated urban settlement in Nairobi, Kenya through population-based surveillance.Surveillance participants were interviewed in their homes every 2 weeks by community interviewers. Participants also had free access to a designated study clinic in the surveillance area where stool specimens were collected from patients with diarrhea (?3 loose stools within 24 hours) or dysentery (?1 stool with visible blood during previous 24 hours). We adjusted crude incidence rates for participants meeting stool collection criteria at household visits who reported visiting another clinic.Shigella species were isolated from 224 (23%) of 976 stool specimens. The overall adjusted incidence rate was 408/100,000 person years of observation (PYO) with highest rates among adults 34-49 years old (1,575/100,000 PYO). Isolates were: Shigella flexneri (64%), S. dysenteriae (11%), S. sonnei (9%), and S. boydii (5%). Over 90% of all Shigella isolates were resistant to trimethoprim-sulfamethoxazole and sulfisoxazole. Additional resistance included nalidixic acid (3%), ciprofloxacin (1%) and ceftriaxone (1%).More than 1 of every 200 persons experience shigellosis each year in this Kenyan urban slum, yielding rates similar to those in some Asian countries. Provision of safe drinking water, improved sanitation, and hygiene in urban slums are needed to reduce disease burden, in addition to development of effective Shigella vaccines. HubMed – drug


Quantitative Assessment of Preventive Behaviors in France during the Fukushima Nuclear Crisis.

PLoS One. 2013; 8(3): e58385
Crépey P, Pivette M, Bar-Hen A

The Fukushima nuclear disaster has generated worldwide concern on the risk of exposure to nuclear radiations. In Europe, health authorities had to issue statements about the lack of usefulness of iodine based preventive treatments within their borders. However a lack of confidence in official messages has developed in various European countries due to recent perceived failures in managing public health crises. The lay population preventive behaviors in this context are largely unknown. Consequently, to examine the effects of public health crisis on lay behaviors leading to pharmaceuticals purchases, we studied the sales of iodine-based products in France before, during and after the crisis.We focused our study on 58 iodine-based drugs available with and without a physician prescription. Our data came from a stratified sample of 3004 pharmacies in metropolitan France. Our study period was from January 2010 to April 2012, with a focus on March-April 2011. We differentiated sales of drugs prescribed by physicians from sales of drugs obtained without a prescription. We used a CUSUM method to detect abnormal increases in sales activity and cross-correlations to assess shifts in sales timing.Sales of iodine-based nutritional complements, and later sales of iodine-based homeopathic remedies, substantially increased (up to 3-fold) during a period of 20 days. Their temporal patterns were correlated to specific events during the crisis. Prescriptions for iodine-based homeopathy increased (up to 35% of all sales). Iodine pills, strictly regulated by health authorities, have also been sold but on a very small scale.These results indicate uncontrolled preventive behaviors resulting in the potentially unjustifiable consumption of available drugs. They have implications in public policy, and demonstrate the usefulness of drug sales surveillance for instantaneous evaluation of population behavior during a global crisis. HubMed – drug