Bridging the Gap between Chemical Reaction Pretraining and Conditional Molecule Generation with a Unified Model

Chemical reactions are the fundamental building blocks of drug design and organic chemistry research. In recent years, there has been a growing need for a large-scale deep-learning framework that can efficiently capture the basic rules of chemical reactions. In this paper, we have proposed a unified framework that addresses both the reaction representation learning and molecule generation tasks, which allows for a more holistic approach. Inspired by the organic chemistry mechanism, we develop a novel pretraining framework that enables us to incorporate inductive biases into the model. Our framework achieves state-of-the-art results on challenging downstream tasks. By possessing chemical knowledge, our generative framework overcome the limitations of current molecule generation models that rely on a small number of reaction templates. In the extensive experiments, our model generates synthesizable drug-like structures of high quality. Overall, our work presents a significant step toward a large-scale deep-learning framework for a variety of reaction-based applications

La interaccion entre iguales como estrategia en los procesos de enseñanza-aprendizaje: Una experiencia con adolescentes.

Inexistenteinfo:eu-repo/semantics/publishedVersio

Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2

Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown. In this study, we generate a structural model of the NUDT9-H domain and identify the binding pocket for ADPR using induced docking and molecular dynamics simulation. We find a subset of 11 residues—H1346, T1347, T1349, L1379, G1389, S1391, E1409, D1431, R1433, L1484, and H1488—that are most likely to directly interact with ADPR. Results from mutagenesis and electrophysiology approaches support the predicted binding mechanism, indicating that ADPR binds tightly to the NUDT9-H domain, and suggest that the most significant interactions are the van der Waals forces with S1391 and L1484, polar solvation interaction with E1409, and electronic interactions (including π–π interactions) with H1346, T1347, Y1349, D1431, and H1488. These findings not only clarify the roles of a range of newly identified residues involved in ADPR binding in the TRPM2 channel, but also reveal the binding pocket for ADPR in the NUDT9-H domain, which should facilitate structure-based drug design for the TRPM2 channel

Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: Meeting new challenges

© 2014 Elsevier Ltd All rights reserved. Despite tremendous successes of GPCR crystallography, the receptors with available structures represent only a small fraction of human GPCRs. An important role of the modeling community is to maximize structural insights for the remaining receptors and complexes. The community-wide GPCR Dock assessment was established to stimulate and monitor the progress in molecular modeling and ligand docking for GPCRs. The four targets in the present third assessment round presented new and diverse challenges for modelers, including prediction of allosteric ligand interaction and activation states in 5-hydroxytryptamine receptors 1B and 2B, and modeling by extremely distant homology for smoothened receptor. Forty-four modeling groups participated in the assessment. State-of-the-art modeling approaches achieved close-to-experimental accuracy for small rigid orthosteric ligands and models built by close homology, and they correctly predicted protein fold for distant homology targets. Predictions of long loops and GPCR activation states remain unsolved problems

Ancient chicken remains reveal the origins of virulence in Marek’s 2 disease virus

The dramatic growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek’s disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the last century. Today, MDV infections kill >90% of unvaccinated birds and controlling it costs >US$1bn annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens

Kang Sehwang's Scenes of Puan Prefecture – describing actual landscape through literati ideals

In the early eighteenth century, chin'gyông "true scenery" or "true view," painting emerged in Chosôn Korea as a dominating landscape genre. While earlier artists were preoccupied with legendary or historical landscapes rooted in Chinese tradition, chin'gyông painters turned their eyes to real landscapes in their own country. This paper centers on a handscroll by Kang Sehwang, Scenes of Puan Prefecture, which is diplayed in the collection of the Los Angeles County Museum of Art. It is not only a major work of the artist in a Western collection but it uniquely combines the "Three Treasure", calligraphy, literature and painting and is thus a superb example of Chosôn literati art. We will investigate the relationship between Kang Sehwang's travelogue and his paintings, trying to shed light on his ideas about traveling itself, about writing travelogues, and about rendering actual scenery. A careful analysis of the handscroll and of related texts, published in his anthology P'yoam yugo (Transmitted Writings by P'yoam), will help us to understand the process of the creation of the scroll and the painter's intention, that is, to understand its position within the context of his life and times.Au début du XVIIIe siècle, la peinture chin'gyông, «vrai paysage » ou «vraie vue », apparaît dans la Corée Chosôn comme dominant le genre du paysage. Alors que les artistes des périodes précédentes étaient préoccupés par les paysages historiques ou légendaires enracinés dans la tradition chinoise, les peintres chin'gyông tournèrent leur regard sur les paysages réels de leur pays. Cet article se concentre sur un rouleau de Kang Sehwang, Scènes du département de Puan, de la collection du Los Angeles County Museum of Art. Celui-ci ne constitue pas uniquement une œuvre majeure de l'artiste au sein d'une collection occidentale, mais il combine de manière unique les «Trois trésors » du lettré, la calligraphie, la littérature et la peinture, et propose ainsi un superbe exemple de l'art littéraire de Chosôn. L'article examine les relations entre le récit de voyage de Kang Sehwang et ses peintures en essayant de faire la lumière sur les idées du peintre sur le voyage lui-même, sur l'écriture de récits de voyages et sur la restitution de paysages réels en peinture. Une analyse attentive du rouleau et des textes qui s'y rapportent, publiés dans l'anthologie de Kang Sehwang P'yoam yugo (Écrits transmis par P'yoam), nous aidera à comprendre le processus de création du rouleau et les intentions de l'auteur, c'est-à-dire à comprendre la position de ce dernier dans le contexte de sa vie et de son temps.Jungmann Burglind, Zhang Liangren. Kang Sehwang's Scenes of Puan Prefecture – describing actual landscape through literati ideals. In: Arts asiatiques, tome 65, 2010. pp. 75-94