Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors

Next generation 3D pharmacophore modeling

3D pharmacophore models are three‐dimensional ensembles of chemically defined interactions of a ligand in its bioactive conformation. They represent an elegant way to decipher chemically encoded ligand information and have therefore become a valuable tool in drug design. In this review, we provide an overview on the basic concept of this method and summarize key studies for applying 3D pharmacophore models in virtual screening and mechanistic studies for protein functionality. Moreover, we discuss recent developments in the field. The combination of 3D pharmacophore models with molecular dynamics simulations could be a quantum leap forward since these approaches consider macromolecule–ligand interactions as dynamic and therefore show a physiologically relevant interaction pattern. Other trends include the efficient usage of 3D pharmacophore information in machine learning and artificial intelligence applications or freely accessible web servers for 3D pharmacophore modeling. The recent developments show that 3D pharmacophore modeling is a vibrant field with various applications in drug discovery and beyond

Mind the Gap - Deciphering GPCR Pharmacology Using 3D Pharmacophores and Artificial Intelligence

G protein-coupled receptors (GPCRs) are amongst the most pharmaceutically relevant and well-studied protein targets, yet unanswered questions in the field leave significant gaps in our understanding of their nuanced structure and function. Three-dimensional pharmacophore models are powerful computational tools in in silico drug discovery, presenting myriad opportunities for the integration of GPCR structural biology and cheminformatics. This review highlights success stories in the application of 3D pharmacophore modeling to de novo drug design, the discovery of biased and allosteric ligands, scaffold hopping, QSAR analysis, hit-to-lead optimization, GPCR de-orphanization, mechanistic understanding of GPCR pharmacology and the elucidation of ligand–receptor interactions. Furthermore, advances in the incorporation of dynamics and machine learning are highlighted. The review will analyze challenges in the field of GPCR drug discovery, detailing how 3D pharmacophore modeling can be used to address them. Finally, we will present opportunities afforded by 3D pharmacophore modeling in the advancement of our understanding and targeting of GPCRs

Gendered Terrorism: The Link Between Sex and Organized Violence

Scholars cite religion, foreign occupation, economic destitution, and lack of opportunity as reasons for terrorism, but gender and masculinity are nearly absent from the conversation. Does masculinity shape the societal structures that foster terrorism? Examining the Taliban in Pakistan and Afghanistan and the Provisional Irish Republican Army (PIRA) in Northern Ireland demonstrates how masculinity establishes the physical spaces that radicalize men and exclude women. It is the force that propels group radicalization and tears apart societies. In scholarship, masculinity is obscured by colonialism and nationalism, but examining masculinity closer illuminates societal constructions that have deep, violent, and political consequences

Transitions in the ageing population

The population with intellectual impairment is ageing, mirroring trends amongst general populations in developed countries. Following a transition from child to adult services, many will increasingly face an extended adult life within which they may benefit from health promoting initiatives. For many, adult life will involve management of long-term conditions. Increasingly people with intellectual impairment will experience age-related disorders and indeed many will acquire their intellectual impairment later in life. All, at whatever age, will potentially move into a phase where care becomes palliative as they near the end of life. This chapter considers health care from this lifespan perspective beginning with the transition from child to adult services

Associations among maternal characteristics, labour interventions, delivery mode and maternal antenatal complications in a NSW large rural town, and comparison to NSW state data

Objective: To determine associations between maternal characteristics, labour interventions, delivery mode and maternal antenatal complications in a NSW rural hospital, and compare these to state data. Methods: Data (maternal characteristics, labour type, delivery mode and maternal antenatal complications) pertaining to women who had delivered a singleton birth at Griffith Base hospital were analysed. Design: Retrospective data analysis of Griffith Base Hospital ‘eMaternity’ database. Setting: Single large rural town in NSW. Participants: Women who delivered a singleton birth between July 2018 and June 2019 inclusive at Griffith Base Hospital. Main outcome measures: 1. Comparison of maternal characteristics of age, BMI, gravida, parity and gestation data between labour type (spontaneous, augmented, induced and planned caesarean section) and delivery modes (vaginal, instrumental vaginal and caesarean section). 2. Associations between labour type, augmentation or induction method, delivery mode and maternal antenatal complications. 3. Multiple regression analysis for influence of age, BMI, parity and labour type on emergency caesarean section outcome. 4. Comparison of maternal, labour and delivery data with NSW state data. Results: Among 457 women, there were higher rates of obesity and spontaneous labour, lower rates of planned caesarean section and augmented labour, and similar rates of induction of labour and emergency caesarean section, compared with NSW. Emergency caesarean section was significantly associated with older age (β = 0.163), and labour augmentation (β = 0.114) and induction (β = 0.169). Labour augmentation with synthetic oxytocin, and induction with balloon catheter, were associated with the highest rates of emergency caesarean section. Conclusion: This large rural town had fewer labour and delivery medical interventions compared with NSW overall. Augmentation and induction of labour contribute to increasing caesarean section rates: directly via associations with emergency caesarean section, and indirectly because previous caesarean section was the most common reason for elective caesarean section

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors

Building America Best Practices Series Volume 15: 40% Whole-House Energy Savings in the Hot-Humid Climate

This best practices guide is the 15th in a series of guides for builders produced by PNNL for the U.S. Department of Energy’s Building America program. This guide book is a resource to help builders design and construct homes that are among the most energy-efficient available, while addressing issues such as building durability, indoor air quality, and occupant health, safety, and comfort. With the measures described in this guide, builders in the hot-humid climate can build homes that have whole-house energy savings of 40% over the Building America benchmark with no added overall costs for consumers. The best practices described in this document are based on the results of research and demonstration projects conducted by Building America’s research teams. Building America brings together the nation’s leading building scientists with over 300 production builders to develop, test, and apply innovative, energy-efficient construction practices. Building America builders have found they can build homes that meet these aggressive energy-efficiency goals at no net increased costs to the homeowners. Currently, Building America homes achieve energy savings of 40% greater than the Building America benchmark home (a home built to mid-1990s building practices roughly equivalent to the 1993 Model Energy Code). The recommendations in this document meet or exceed the requirements of the 2009 IECC and 2009 IRC and those requirements are highlighted in the text. Requirements of the 2012 IECC and 2012 IRC are also noted in text and tables throughout the guide. This document will be distributed via the DOE Building America website: www.buildingamerica.gov

Mind the Gap—Deciphering GPCR Pharmacology Using 3D Pharmacophores and Artificial Intelligence

G protein-coupled receptors (GPCRs) are amongst the most pharmaceutically relevant and well-studied protein targets, yet unanswered questions in the field leave significant gaps in our understanding of their nuanced structure and function. Three-dimensional pharmacophore models are powerful computational tools in in silico drug discovery, presenting myriad opportunities for the integration of GPCR structural biology and cheminformatics. This review highlights success stories in the application of 3D pharmacophore modeling to de novo drug design, the discovery of biased and allosteric ligands, scaffold hopping, QSAR analysis, hit-to-lead optimization, GPCR de-orphanization, mechanistic understanding of GPCR pharmacology and the elucidation of ligand–receptor interactions. Furthermore, advances in the incorporation of dynamics and machine learning are highlighted. The review will analyze challenges in the field of GPCR drug discovery, detailing how 3D pharmacophore modeling can be used to address them. Finally, we will present opportunities afforded by 3D pharmacophore modeling in the advancement of our understanding and targeting of GPCRs