| 1. |
- Alao, John Patrick, 1973
(författare)
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The ATM regulated DNA damage response pathway as a chemo- and radiosensitisation target
- 2009
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Ingår i: Expert Opinion on Drug Discovery. - : Informa Healthcare. - 1746-0441 .- 1746-045X. ; 4:5, s. 495-505
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Forskningsöversikt (refereegranskat)abstract
- Background: Ataxia telangiectasia mutated (ATM) kinase plays a central role in maintaining genomic stability and regulating the response of cells exposed to agents that induce DNA damage. ATM regulated pathways also enable cancer cells to resist the lethal effects of genotoxic cancer treatments. The pharmacological inhibition of these pathways may thus sensitise cancer cells to chemo- and radiotherapy. Objectives: This review outlines the role of ATM in regulating components of the DNA damage response pathway. The potential of inhibitors that target ATM regulated pathways to act as chemo- and radiosensitising agents is also discussed. Results/conclusions: Inhibitors that target ATM and its downstream targets are likely to be effective as chemo- and/ or radiosensitising agents. Their effective use will, however, require a better understanding of when and how ATM influences the sensitivity of cancer cells to particular genotoxic agents.
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| 2. |
- Bondarev, Andrey D., et al.
(författare)
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Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions
- 2020
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Ingår i: Expert Opinion on Drug Discovery. - : TAYLOR & FRANCIS LTD. - 1746-0441 .- 1746-045X. ; 15:11, s. 1291-1307
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Forskningsöversikt (refereegranskat)abstract
- Introduction: The G protein-coupled receptors (GPCR) superfamily is among the most widely exploited targets for therapeutics, with drugs mainly targeting the Rhodopsin, Glutamate and Secretin family receptors. The receptors of the Adhesion family, however, remain comparatively unexplored in this aspect. This review aims to discuss the druggability of Adhesion GPCRs (aGPCR), highlighting the relevant opportunities and challenges.Areas Covered: In this review, the authors provide a disease-oriented summary of aGPCR involvement in humans and discuss the current status of characterizing therapeutic agents with a focus on new opportunities using low molecular weight substances.Expert opinion: The small molecule antagonist dihydromunduletone and partial agonist 3-alpha-acetoxydihydrodeoxygedunin, along with the endogenous natural ligand synaptamide currently comprise some of the most important discoveries made in an attempt to characterize aGPCR druggability. The small molecule modulators provide important insights regarding the structure-activity relationship and suggest that targeting the tethered peptide agonist results in a nonselective pharmacological action, while synaptamide may be considered a potentially attractive tool to achieve a higher degree of selectivity.
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| 4. |
- Genheden, Samuel, et al.
(författare)
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The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities
- 2015
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Ingår i: Expert Opinion on Drug Discovery. - : Informa Healthcare. - 1746-0441 .- 1746-045X. ; 10:5, s. 449-461
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Forskningsöversikt (refereegranskat)abstract
- Introduction: The molecular mechanics energies combined with the Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success. Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications. Expert opinion: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results.
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| 8. |
- Porosk, Ly, et al.
(författare)
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Approaches for the discovery of new cell-penetrating peptides
- 2021
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Ingår i: Expert Opinion on Drug Discovery. - : Informa UK Limited. - 1746-0441 .- 1746-045X. ; 16:5, s. 553-565
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Forskningsöversikt (refereegranskat)abstract
- Introduction: The capability of cell-penetrating peptides (CPP), also known as protein transduction domains (PTD), to enter into cells possibly with an attached cargo, makes their application as delivery vectors or as direct therapeutics compelling. They are generally biocompatible, nontoxic, and easy to synthesize and modify. Three decades after the discovery of the first CPPs, similar to 2,000 CPP sequences have been identified, and many more predicted. Nevertheless, the field has a strong commitment to authenticate new, more efficient, and specific CPPs. Areas covered: Although a scattering of CPPs have been found by chance, various systematic approaches have been developed and refined over the years to directly aid the identification and depiction of new peptide-based delivery vectors or therapeutics. Here, the authors give an overview of CPPs, and review various approaches of discovering new ones. An emphasis is placed on in silico methods, as these have advanced rapidly in recent years. Expert opinion: Although there are many known CPPs, there is a need to find more efficient and specific CPPs. Several approaches are used to identify such sequences. The success of these approaches depends on the advancement of others and the successful prediction of CPP sequences relies on experimental data.
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| 9. |
- Prachayasittikul, Veda, et al.
(författare)
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Exploring the epigenetic drug discovery landscape
- 2017
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Ingår i: Expert Opinion on Drug Discovery. - : TAYLOR & FRANCIS LTD. - 1746-0441 .- 1746-045X. ; 12:4, s. 345-362
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Epigenetic modification has been implicated in a wide range of diseases and the ability to modulate such systems is a lucrative therapeutic strategy in drug discovery. Areas covered: This article focuses on the concepts and drug discovery aspects of epigenomics. This is achieved by providing a survey of the following concepts: (i) factors influencing epigenetics, (ii) diseases arising from epigenetics, (iii) epigenetic enzymes as druggable targets along with coverage of existing FDA-approved drugs and pharmacological agents, and (iv) drug repurposing/repositioning as a means for rapid discovery of pharmacological agents targeting epigenetics. Expert opinion: Despite significant interests in targeting epigenetic modifiers as a therapeutic route, certain classes of target proteins are heavily studied while some are less characterized. Thus, such orphan target proteins are not yet druggable with limited report of active modulators. Current research points towards a great future with novel drugs directed to the many complex multifactorial diseases of humans, which are still often poorly understood and difficult to treat.
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| 10. |
- Quist, Arjan P., et al.
(författare)
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Micropatterned surfaces : techniques and applications in cell biology
- 2010
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Ingår i: Expert Opinion on Drug Discovery. - : Informa Healthcare. - 1746-0441 .- 1746-045X. ; 5:6, s. 569-581
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Forskningsöversikt (refereegranskat)abstract
- Importance of the field: Engineering of cell culture substrates provides a unique opportunity for precise control of the cellular microenvironment with both spatial as well as temporal resolutions. This greatly enhances studies of cell-cell, cell-matrix and cell-factor interaction studies in vitro. Areas covered in this review: The technologies used for micropatterning in the biological field over the last decade and new applications in the last few years for dynamic control of surfaces, tissue engineering, drug discovery, cell-cell interactions and stem cell studies are presented. What the reader will gain: The reader will gain knowledge on the state of the art in micropatterning and its wide ranging applications in cell patterning, with new pathways to control the cell environment. Take home message: Micropatterning of cells has been studied and developed enough to be widely applied ranging from single cell assays to tissue engineering. Techniques have evolved from many-step processes to direct writing of biologically selective patterns.
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| 12. |
- Spjuth, Ola, Professor, 1977-, et al.
(författare)
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The machine learning life cycle and the cloud : implications for drug discovery.
- 2021
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Ingår i: Expert Opinion on Drug Discovery. - : Taylor & Francis. - 1746-0441 .- 1746-045X. ; 16:9, s. 1071-1079
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Artificial intelligence (AI) and machine learning (ML) are increasingly used in many aspects of drug discovery. Larger data sizes and methods such as Deep Neural Networks contribute to challenges in data management, the required software stack, and computational infrastructure. There is an increasing need in drug discovery to continuously re-train models and make them available in production environments.Areas covered: This article describes how cloud computing can aid the ML life cycle in drug discovery. The authors discuss opportunities with containerization and scientific workflows and introduce the concept of MLOps and describe how it can facilitate reproducible and robust ML modeling in drug discovery organizations. They also discuss ML on private, sensitive and regulated data.Expert opinion: Cloud computing offers a compelling suite of building blocks to sustain the ML life cycle integrated in iterative drug discovery. Containerization and platforms such as Kubernetes together with scientific workflows can enable reproducible and resilient analysis pipelines, and the elasticity and flexibility of cloud infrastructures enables scalable and efficient access to compute resources. Drug discovery commonly involves working with sensitive or private data, and cloud computing and federated learning can contribute toward enabling collaborative drug discovery within and between organizations.Abbreviations: AI = Artificial Intelligence; DL = Deep Learning; GPU = Graphics Processing Unit; IaaS = Infrastructure as a Service; K8S = Kubernetes; ML = Machine Learning; MLOps = Machine Learning and Operations; PaaS = Platform as a Service; QC = Quality Control; SaaS = Software as a Service.
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| 13. |
- Vistoli, Giulio, et al.
(författare)
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MEDIATE - Molecular DockIng at homE: Turning collaborative simulations into therapeutic solutions
- 2023
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Ingår i: Expert Opinion on Drug Discovery. - : Taylor and Francis Ltd.. - 1746-0441 .- 1746-045X. ; 18:8, s. 821-833
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Collaborative computing has attracted great interest in the possibility of joining the efforts of researchers worldwide. Its relevance has further increased during the pandemic crisis since it allows for the strengthening of scientific collaborations while avoiding physical interactions. Thus, the E4C consortium presents the MEDIATE initiative which invited researchers to contribute via their virtual screening simulations that will be combined with AI-based consensus approaches to provide robust and method-independent predictions. The best compounds will be tested, and the biological results will be shared with the scientific community. Areas covered: In this paper, the MEDIATE initiative is described. This shares compounds’ libraries and protein structures prepared to perform standardized virtual screenings. Preliminary analyses are also reported which provide encouraging results emphasizing the MEDIATE initiative’s capacity to identify active compounds. Expert opinion: Structure-based virtual screening is well-suited for collaborative projects provided that the participating researchers work on the same input file. Until now, such a strategy was rarely pursued and most initiatives in the field were organized as challenges. The MEDIATE platform is focused on SARS-CoV-2 targets but can be seen as a prototype which can be utilized to perform collaborative virtual screening campaigns in any therapeutic field by sharing the appropriate input files.
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| 14. |
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| 15. |
- Öhnstedt, Emelie, et al.
(författare)
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The discovery and development of topical medicines for wound healing
- 2019
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Ingår i: Expert Opinion on Drug Discovery. - : Taylor & Francis. - 1746-0441 .- 1746-045X. ; 14:5, s. 485-497
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Forskningsöversikt (refereegranskat)abstract
- Introduction: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized countries, and the incidence is rising. Currently, two parallel trends influence innovations within the field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of health economy and value-based models.Areas covered: This review focuses on the discovery of drug candidates and development of treatments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing wounds.Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline.
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| 16. |
- Norrby, Klas, 1937
(författare)
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Drug testing with angiogenesis models
- 2008
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Ingår i: Expert Opinion On Drug Discovery. - 1746-0441. ; 3:5, s. 533-549
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Forskningsöversikt (refereegranskat)
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