Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators ...were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.
Pharmacophore‐based virtual screening (VS) has emerged as an efficient computer‐aided drug design technique when appraising multiple ligands with similar structures or targets with unknown crystal ...structures. Current pharmacophore modeling and analysis software suffers from inadequate integration of mainstream methods and insufficient user‐friendly program interface. In this study, we propose a stand‐alone, integrated, graphical software for pharmacophore‐based VS, termed ePharmer. Both ligand‐based and structure‐based pharmacophore generation methods were integrated into a compact architecture. Fine‐grained modules were carefully organized into the computing, integration, and visualization layers. Graphical design covered the global user interface and specific user operations including editing, evaluation, and task management. Metabolites prediction analysis with the chosen VS result is provided for preselection of wet experiments. Moreover, the underlying computing units largely adopted the preliminary work of our research team. The presented software is currently in client use and will be released for both professional and nonexpert users. Experimental results verified the favorable computing capability, user convenience, and case performance of the proposed software.
The pharmacophores are efficiently generated according to two different inputs, the ligand and the protein. The top n small molecules with the best matches (highest scores) are virtually screened through PharmFit algorithm from the small molecule database. The sorted small molecules and metabolites prediction are visualized for intuitive understanding and further analysis. Well‐designed user interface conveniently assists users to interactive operations including editing, evaluation and task management.
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer’s disease patients while minimizing the cholinergic ...side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
Immigrants face the challenge of obtaining culturally specific health information and adapting to a new healthcare system. Through qualitative content analysis, this study explores how Chinese ...immigrant mothers use the ethnic social media—WeChat to engage in health information sharing and coping with cultural differences in healthcare between the U.S. and China. Based on the data collected from one WeChat group in a metropolitan city in the northeastern U.S., Chinese immigrant mothers frequently discuss the topics of “doctors and hospitals,” “insurance and cost,” “medicine and treatment,” and “alternative health care.” They constantly compare Chinese health care beliefs and practices with western ones. They adopt various acculturation strategies to manage the cultural differences in healthcare beliefs, practices, and systems. We call for future research to further examine immigrants’ health information sharing via social media and consider acculturation as coping strategies or processes in the health communication context.
One major challenge in the design of highly multiplexed PCR primer sets is the large number of potential primer dimer species that grows quadratically with the number of primers to be designed. ...Simultaneously, there are exponentially many choices for multiplex primer sequence selection, resulting in systematic evaluation approaches being computationally intractable. Here, we present and experimentally validate Simulated Annealing Design using Dimer Likelihood Estimation (SADDLE), a stochastic algorithm for design of multiplex PCR primer sets that minimize primer dimer formation. In a 96-plex PCR primer set (192 primers), the fraction of primer dimers decreases from 90.7% in a naively designed primer set to 4.9% in our optimized primer set. Even when scaling to 384-plex (768 primers), the optimized primer set maintains low dimer fraction. In addition to NGS, SADDLE-designed primer sets can also be used in qPCR settings to allow highly multiplexed detection of gene fusions in cDNA, with a single-tube assay comprising 60 primers detecting 56 distinct gene fusions recurrently observed in lung cancer.
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