Automated high throughput pKa and distribution coefficient measurements of pharmaceutical compounds for the SAMPL8 blind prediction challenge.

The goal of the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) challenge is to improve the accuracy of current computational models to estimate free energy of binding, deprotonation, distribution and other associated physical properties that are useful for the design of new pharmaceutical products. New experimental datasets of physicochemical properties provide opportunities for prospective evaluation of computational prediction methods. Here, aqueous pKa and a range of bi-phasic logD values for a variety of pharmaceutical compounds were determined through a streamlined automated process to be utilized in the SAMPL8 physical property challenge. The goal of this paper is to provide an in-depth review of the experimental methods utilized to create a comprehensive data set for the blind prediction challenge. The significance of this work involves the use of high throughput experimentation equipment and instrumentation to produce acid dissociation constants for twenty-three drug molecules, as well as distribution coefficients for eleven of those molecules.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

Effect of Probiotics on the Incidence of Healthcare-Associated Infections in Mechanically Ventilated Neurocritical Care Patients.

BACKGROUND: Healthcare-associated infections (HAIs) are seen in 17% of critically ill patients. Probiotics, live nonpathogenic microorganisms, may aid in reducing the incidence of infection in critically ill patients. We hypothesized that administration of probiotics would be safe and reduce the incidence of HAIs among mechanically ventilated neurocritical care patients. METHODS: We assembled 2 retrospective cohorts of mechanically ventilated neurocritical care patients. In the preintervention cohort from July 1, 2011, to December 31, 2011, probiotics were not used. In the postintervention group from July 1, 2012, to December 31, 2012, 1 g of a combination of Lactobacillus acidophilus and Lactobacillus helveticus was administered twice daily to all patients who were mechanically ventilated for more than 24 hours. RESULTS: There were a total of 167 patients included, 80 patients in the preintervention group and 87 patients in the postintervention group. No patients in the preintervention group received probiotics. Eighty-five (98%) patients in the postintervention group received probiotics for a median of 10 days (interquartile range, 4-20 days). There were 14 (18%) HAIs in the preintervention group and 8 (9%) HAIs in the postintervention group (P = .17). Ventilator days, lengths of stay, in-hospital mortality, and discharge disposition were similar between the pre- and postintervention groups. There were no cases of Lactobacillus bacteremia or other adverse events associated with probiotics use. CONCLUSION: Probiotics are safe to administer in neurocritical care patients; however, this study failed to demonstrate a significant decrease in HAIs or secondary outcomes associated with probiotics.

Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy.

Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele ("risk allele") may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (L(A)/L(G)/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication.

The HepaRG cell line: a unique in vitro tool for understanding drug metabolism and toxicology in human.

INTRODUCTION: HepaRG is a unique cell line showing a great plasticity, which differentiates to both canaliculae-like and hepatocyte-like cells. The long-term stability of key cell functions, for example, the drug-metabolizing cytochrome P450 (CYP) enzyme activities, in culture is especially useful in drug metabolism, disposition and toxicity studies. AREAS COVERED: This review describes features of the HepaRG cells focusing on drug-metabolizing enzymes and drug transporters, their functionality and regulation. Several applications in drug discovery studies are discussed and the use of HepaRG, as a human relevant predictive in vitro CYP induction model, is described. In addition, promising studies using HepaRG cells for understanding liver toxicity mechanisms by drug compounds are also discussed. EXPERT OPINION: HepaRG cells exhibit features which make them useful as an in vitro model for drug metabolism, disposition and toxicity studies, and could, for many studies, replace the requirement for primary human hepatocytes. Care should be taken since HepaRG cells are of a specific genotype which is reflected in the expression of drug processing proteins. The finding that HepaRG cells form tight junctions provides the basis for formation of functional canalicular structures and this should be investigated further to aid development of human relevant hepatic in vitro 2D and 3D models.