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Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library.

ABSTRACT: Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.

SUBMITTER: Canal-Martin A

PROVIDER: S-EPMC6595003 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library.

Canal-Martín Andrea A Sastre Javier J Sánchez-Barrena María José MJ Canales Angeles A Baldominos Sara S Pascual Naiara N Martínez-González Loreto L Molero Dolores D Fernández-Valle Mª Encarnación ME Sáez Elena E Blanco-Gabella Patricia P Gómez-Rubio Elena E Martín-Santamaría Sonsoles S Sáiz Almudena A Mansilla Alicia A Cañada F Javier FJ Jiménez-Barbero Jesús J Martínez Ana A Pérez-Fernández Ruth R

Nature communications 20190626 1

Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction interm ...[more]

PMID: 31243268

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Project description:Underwater sensor networks represent an important and promising field of research due to the large diversity of underwater ubiquitous applications that can be supported by these networks, e.g., systems that deliver tsunami and oil spill warnings, or monitor submarine ecosystems. Most of these monitoring and warning systems require real-time communication in wide area networks that have a low density of nodes. The underwater communication medium involved in these networks is very harsh and imposes strong restrictions to the communication process. In this scenario, the real-time transmission of information is done mainly using acoustic signals, since the network nodes are not physically close. The features of the communication scenario and the requirements of the communication process represent major challenges for designers of both, communication protocols and monitoring and warning systems. The lack of models to represent these networks is the main stumbling block for the proliferation of underwater ubiquitous systems. This paper presents a real-time communication model for underwater acoustic sensor networks (UW-ASN) that are designed to cover wide areas with a low density of nodes, using any-to-any communication. This model is analytic, considers two solution approaches for scheduling the real-time messages, and provides a time-constraint analysis for the network performance. Using this model, the designers of protocols and underwater ubiquitous systems can quickly prototype and evaluate their solutions in an evolving way, in order to determine the best solution to the problem being addressed. The suitability of the proposal is illustrated with a case study that shows the performance of a UW-ASN under several initial conditions. This is the first analytic model for representing real-time communication in this type of network, and therefore, it opens the door for the development of underwater ubiquitous systems for several application scenarios.

Dataset Information

Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library.

Publications

Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library.

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