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- Bender, Andreas, et al.
(författare)
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Evaluation guidelines for machine learning tools in the chemical sciences
- 2022
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Ingår i: Nature Reviews Chemistry. - : Springer Science and Business Media LLC. - 2397-3358. ; 6:6, s. 428-442
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Tidskriftsartikel (refereegranskat)abstract
- Machine learning (ML) promises to tackle the grand challenges in chemistry and speed up the generation, improvement and/or ordering of research hypotheses. Despite the overarching applicability of ML workflows, one usually finds diverse evaluation study designs. The current heterogeneity in evaluation techniques and metrics leads to difficulty in (or the impossibility of) comparing and assessing the relevance of new algorithms. Ultimately, this may delay the digitalization of chemistry at scale and confuse method developers, experimentalists, reviewers and journal editors. In this Perspective, we critically discuss a set of method development and evaluation guidelines for different types of ML-based publications, emphasizing supervised learning. We provide a diverse collection of examples from various authors and disciplines in chemistry. While taking into account varying accessibility across research groups, our recommendations focus on reporting completeness and standardizing comparisons between tools. We aim to further contribute to improved ML transparency and credibility by suggesting a checklist of retro-/prospective tests and dissecting their importance. We envisage that the wide adoption and continuous update of best practices will encourage an informed use of ML on real-world problems related to the chemical sciences. [Figure not available: see fulltext.]
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| 3. |
- Corbella Morató, Marina, et al.
(författare)
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Loop dynamics and the evolution of enzyme activity
- 2023
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 7:8, s. 536-547
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Forskningsöversikt (refereegranskat)abstract
- In the early 2000s, Tawfik presented his 'New View' on enzyme evolu-tion, highlighting the role of conformational plasticity in expanding the functional diversity of limited repertoires of sequences. This view is gaining increasing traction with increasing evidence of the importance of conformational dynamics in both natural and laboratory evolution of enzymes. The past years have seen several elegant examples of harnessing conformational (particularly loop) dynamics to successfully manipulate protein function. This Review revisits flexible loops as critical participants in regulating enzyme activity. We showcase several systems of particular interest: triosephosphate isomerase barrel proteins, protein tyrosine phosphatases and beta-lactamases, while briefly discussing other systems in which loop dynamics are important for selectivity and turnover. We then discuss the implications for engineering, presenting examples of successful loop manipulation in either improving catalytic efficiency, or changing selectivity completely. Overall, it is becoming clearer that mimicking nature by manipulating the conformational dynamics of key protein loops is a powerful method of tailoring enzyme activity, without needing to target active-site residues. [GRAPHICS] .
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| 4. |
- Guillemard, Lucas, et al.
(författare)
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Late-stage C-H functionalization offers new opportunities in drug discovery
- 2021
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Ingår i: Nature Reviews Chemistry. - : Springer Science and Business Media LLC. - 2397-3358. ; 5:8, s. 522-545
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Forskningsöversikt (refereegranskat)abstract
- Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C-H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C-H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C-H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C-H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest.
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| 5. |
- Jorner, Kjell, et al.
(författare)
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Organic reactivity from mechanism to machine learning
- 2021
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:4, s. 240-255
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Forskningsöversikt (refereegranskat)abstract
- As more data are introduced in the building of models of chemical reactivity, the mechanistic component can be reduced until 'big data' applications are reached. These methods no longer depend on underlying mechanistic hypotheses, potentially learning them implicitly through extensive data training. Reactivity models often focus on reaction barribers, but can also be trained to directly predict lab-relevant properties, such as yields or conditions. Calculations with a quantum-mechanical component are still preferred for quantitative predictions of reactivity. Although big data applications tend to be more qualitative, they have the advantage to be broadly applied to different kinds of reactions. There is a continuum of methods in between these extremes, such as methods that use quantum-derived data or descriptors in machine learning models. Here, we present an overview of the recent machine learning applications in the field of chemical reactivity from a mechanistic perspective. Starting with a summary of how reactivity questions are addressed by quantum-mechanical methods, we discuss methods that augment or replace quantum-based modelling with faster alternatives relying on machine learning.
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| 7. |
- Miethke, Marcus, et al.
(författare)
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Towards the sustainable discovery and development of new antibiotics
- 2021
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:10, s. 726-749
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Forskningsöversikt (refereegranskat)abstract
- An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
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| 8. |
- Phan, Nhu TN, 1981, et al.
(författare)
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Measuring synaptic vesicles using cellular electrochemistry and nanoscale molecular imaging
- 2017
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Ingår i: Nature Reviews Chemistry. - : Springer Science and Business Media LLC. - 2397-3358. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- The synaptic vesicle, a cellular compartment tens to hundreds of nanometres in size, is a main player in the process of exocytosis for neuronal communication. Understanding the regulatory mechanism of neurotransmission and neurological disorders requires the quantification of chemicals transmitted between cells. These challenging single vesicle measurements can be performed using analytical techniques described in this Review. In vivo amperometry at living cells can be used to quantify the amount of neurotransmitter released from a vesicle. By contrast, intracellular vesicle impact electrochemical cytometry allows the amount of molecules to be determined inside single vesicles. Although the dominant mode of exocytosis from vesicles is still under debate, several experiments point to the importance of partial release modes. Making use of fluorescent or isotopically labelled probes enables super-resolution optical and mass spectrometric imaging of molecular composition and activity of single vesicles. Correlating results from these nanoscopic techniques with those from electrochemistry has proved advantageous in understanding the relationship between vesicle structure and function. © 2017 Macmillan Publishers Limited.
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| 9. |
- Poongavanam, Vasanthanathan, Docent, et al.
(författare)
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Molecular chameleons in drug discovery
- 2024
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 8, s. 45-60
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Forskningsöversikt (refereegranskat)abstract
- Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design.
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| 10. |
- Questell-Santiago, Ydna M., et al.
(författare)
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Stabilization strategies in biomass depolymerization using chemical functionalization
- 2020
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Ingår i: Nature Reviews Chemistry. - : Springer Science and Business Media LLC. - 2397-3358. ; 4:6, s. 311-330
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Tidskriftsartikel (refereegranskat)abstract
- A central feature of most lignocellulosic-biomass-valorization strategies is the depolymerization of all its three major constituents: cellulose and hemicellulose to simple sugars, and lignin to phenolic monomers. However, reactive intermediates, generally resulting from dehydration reactions, can participate in undesirable condensation pathways during biomass deconstruction, which have posed fundamental challenges to commercial biomass valorization. Thus, new strategies specifically aim to suppress condensations of reactive intermediates, either avoiding their formation by functionalizing the native structure or intermediates or selectively transforming these intermediates into stable derivatives. These strategies have provided unforeseen upgrading pathways, products and process solutions. In this Review, we outline the molecular driving forces that shape the deconstruction landscape and describe the strategies for chemical functionalization. We then offer an outlook on further developments and the potential of these strategies to sustainably produce renewable-platform chemicals.
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