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.
This article is categorized under:
Computer and Information Science > Chemoinformatics
Computer and Information Science > Computer Algorithms and Programming
Molecular and Statistical Mechanics > Molecular Interactions
3D pharmacophores have become an essential technique for in silico drug discovery. Recent algorithmic advances with respect to machine learning and molecular dynamics simulations as well as increased availability of computing resources allowed the evolution of classic pharmacophore modeling techniques toward powerful flexibility‐ and knowledge‐enriched techniques.
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.
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.
Abstract
Objective
Numerous studies indicate that the social determinants of health (SDOH), conditions in which people work, play, and learn, account for 30%–55% of health outcomes. Many healthcare ...and social service organizations seek ways to collect, integrate, and address the SDOH. Informatics solutions such as standardized nursing terminologies may facilitate such goals. In this study, we compared one standardized nursing terminology, the Omaha System, in its consumer-facing form, Simplified Omaha System Terms (SOST), to social needs screening tools identified by the Social Interventions Research and Evaluation Network (SIREN).
Materials and Methods
Using standard mapping techniques, we mapped 286 items from 15 SDOH screening tools to 335 SOST challenges. The SOST assessment includes 42 concepts across 4 domains. We analyzed the mapping using descriptive statistics and data visualization techniques.
Results
Of the 286 social needs screening tools items, 282 (98.7%) mapped 429 times to 102 (30.7%) of the 335 SOST challenges from 26 concepts in all domains, most frequently from Income, Home, and Abuse. No single SIREN tool assessed all SDOH items. The 4 items not mapped were related to financial abuse and perceived quality of life.
Discussion
SOST taxonomically and comprehensively collects SDOH data compared to SIREN tools. This demonstrates the importance of implementing standardized terminologies to reduce ambiguity and ensure the shared meaning of data.
Conclusions
SOST could be used in clinical informatics solutions for interoperability and health information exchange, including SDOH. Further research is needed to examine consumer perspectives regarding SOST assessment compared to other social needs screening tools.
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-HT
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.
This study aimed to systematically identify, appraise and synthesize qualitative evidence which explored fathers' experiences and perspectives of their partners' postpartum psychosis.
Qualitative ...evidence synthesis (QES).
Seven databases (CINAHL, PsycINFO, Medline, Scopus, Google Scholar, ProQuest Dissertations and Open Grey) were systematically searched for qualitative studies from each database's inception to the 17th of February 2022.
Studies that utilized a qualitative research design to explore fathers' experiences and perspectives of their partners' postpartum psychosis were included. Studies were appraised using the Critical Appraisal Skills Programme to determine their methodological quality. Qualitative data were extracted and synthesized using the process of thematic synthesis to form analytical themes.
Eleven reports (seven journal articles and four theses), representing six unique qualitative studies were included in the review. Two analytical themes and eight subthemes were identified. The analytical themes were 'a sense of loss across multiple domains of their lives', and 'informational and emotional support needs'.
Postpartum psychosis is a severe mental health condition which also impacts the woman's partner. Fathers experienced an array of emotions which they attributed to a lack of knowledge and understanding of postpartum psychosis. The development of appropriate support structures is needed to better support fathers in supporting their partners.
This review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement and ENTREQ reporting guidelines.
There was no patient or public contribution.
WHAT PROBLEM DID THIS STUDY ADDRESS?: Fathers play a pivotal role in supporting their partner who has postpartum psychosis, and a supportive father has a positive impact on the mental health of the mother. Several qualitative studies have explored fathers' experiences of their partners' psychosis. This QES integrated findings from these studies to gain a deeper understanding and knowledge of the father's experience. WHAT ARE THE MAIN FINDINGS?: Fathers reported a significant sense of loss across multiple domains of their lives, from a perceived loss of their relationship with their partner to a loss of the future they had planned together. Fathers experienced an array of emotions, such as fear and shock which they attributed to their lack of knowledge and awareness of postpartum psychosis. WHERE AND ON WHOM WILL THIS RESEARCH HAVE AN IMPACT?: This review provides a deeper insight and understanding into the father's experiences and perspectives of their partners' postpartum psychosis. This insight can inform healthcare professionals and policymakers in the development of appropriate support structures which meet the needs of this population. The provision of appropriate support structures could have a positive impact on the father's well-being and ability to support their partner.
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.
Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage
. The FA repair pathway protects against ...endogenous and exogenous carcinogenic aldehydes
. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas
(SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus
(HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.
The genomic organization of the human protocadherin alpha, beta, and gamma gene clusters (designated Pcdh alpha gene symbol PCDHA, Pcdh beta PCDHB, and Pcdh gamma PCDHG) is remarkably similar to that ...of immunoglobulin and T-cell receptor genes. The extracellular and transmembrane domains of each protocadherin protein are encoded by an unusually large "variable" region exon, while the intracellular domains are encoded by three small "constant" region exons located downstream from a tandem array of variable region exons. Here we report the results of a comparative DNA sequence analysis of the orthologous human (750 kb) and mouse (900 kb) protocadherin gene clusters. The organization of Pcdh alpha and Pcdh gamma gene clusters in the two species is virtually identical, whereas the mouse Pcdh beta gene cluster is larger and contains more genes than the human Pcdh beta gene cluster. We identified conserved DNA sequences upstream of the variable region exons, and found that these sequences are more conserved between orthologs than between paralogs. Within this region, there is a highly conserved DNA sequence motif located at about the same position upstream of the translation start codon of each variable region exon. In addition, the variable region of each gene cluster contains a rich array of CpG islands, whose location corresponds to the position of each variable region exon. These observations are consistent with the proposal that the expression of each variable region exon is regulated by a distinct promoter, which is highly conserved between orthologous variable region exons in mouse and human.
In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality ...chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization,
in vitro
–
in vivo
correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.
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