Global Analysis of Small Molecule Binding to Related Protein Targets

We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

Clinical Outcomes and Complications of Pituitary Blastoma.

This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Clinical Endocrinology & Metabolism, following peer review. The version of record: Anthony P Y Liu, Megan M Kelsey, Nelly Sabbaghian, Sung-Hye Park, Cheri L Deal, Adam J Esbenshade, Oswald Ploner, Andrew Peet, Heidi Traunecker, Yomna H E Ahmed, Margaret Zacharin, Anatoly Tiulpakov, Anastasia M Lapshina, Andrew W Walter, Pinaki Dutta, Ashutosh Rai, Márta Korbonits, Leanne de Kock, Kim E Nichols, William D Foulkes, John R Priest, Clinical Outcomes and Complications of Pituitary Blastoma, The Journal of Clinical Endocrinology & Metabolism, , dgaa857, https://doi.org/10.1210/clinem/dgaa857 is available online at: https://doi.org/10.1210/clinem/dgaa857CONTEXT: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. OBJECTIVE: To describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases.Design and Setting: Multi-institutional case series from tertiary pediatric oncology centers. PATIENTS: Children with pituitary blastoma. INTERVENTIONS: Genetic testing, surgery, oncologic therapy, endocrine support. OUTCOME MEASURES: Survival, long-term morbidities, germline and tumor DICER1 genotypes. RESULTS: Seventeen pituitary blastoma cases were studied (10 female and 7 male); median age at diagnosis was 11 months (range 2-24). Cushing syndrome was the most frequent presentation (n=10). Cushingoid stigmata were absent in seven children (two with raised ACTH; five with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n=7), subtotal resection (n=9), and biopsy (n=1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, nine patients were alive; eight patients died of early medical/surgical complications (n=3), sepsis (n=1), catheter-related complication (n=1), aneurysmal bleeding (n=1), second brain tumor (n=1), and progression (n=1). Surgery was the only intervention for five of nine survivors. Extent of resection, but neither Ki67 labelling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n=8), visual (n=4), and neurodevelopmental (n=3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. CONCLUSIONS: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management