775 research outputs found
Selection of Color-Changing and Intensity-Increasing Fluorogenic Probe as Protein-Specific Indicator Obtained via the 10BASEd-T
To obtain a molecular probe for specific protein detection, we have synthesized fluorogenic probe library of vastdiversity on bacteriophage T7 via the gp10 based-thioetherificaion (10BASEd-T). A remarkable color-changing and turning-on probewas selected from the library, and its physicochemical properties upon target-specific binding were obtained. Combination analysesof fluorescence emission titration, isothermal titration calorimetry (ITC), and quantitative saturation-transfer difference (STD) NMRmeasurements followed by in silico docking simulation, rationalized most plausible geometry of the ligand-protein interaction
T-Rex: Text-assisted Retrosynthesis Prediction
As a fundamental task in computational chemistry, retrosynthesis prediction
aims to identify a set of reactants to synthesize a target molecule. Existing
template-free approaches only consider the graph structures of the target
molecule, which often cannot generalize well to rare reaction types and large
molecules. Here, we propose T-Rex, a text-assisted retrosynthesis prediction
approach that exploits pre-trained text language models, such as ChatGPT, to
assist the generation of reactants. T-Rex first exploits ChatGPT to generate a
description for the target molecule and rank candidate reaction centers based
both the description and the molecular graph. It then re-ranks these candidates
by querying the descriptions for each reactants and examines which group of
reactants can best synthesize the target molecule. We observed that T-Rex
substantially outperformed graph-based state-of-the-art approaches on two
datasets, indicating the effectiveness of considering text information. We
further found that T-Rex outperformed the variant that only use ChatGPT-based
description without the re-ranking step, demonstrate how our framework
outperformed a straightforward integration of ChatGPT and graph information.
Collectively, we show that text generated by pre-trained language models can
substantially improve retrosynthesis prediction, opening up new avenues for
exploiting ChatGPT to advance computational chemistry. And the codes can be
found at https://github.com/lauyikfung/T-Rex
Learning Graph Models for Retrosynthesis Prediction
Retrosynthesis prediction is a fundamental problem in organic synthesis,
where the task is to identify precursor molecules that can be used to
synthesize a target molecule. A key consideration in building neural models for
this task is aligning model design with strategies adopted by chemists.
Building on this viewpoint, this paper introduces a graph-based approach that
capitalizes on the idea that the graph topology of precursor molecules is
largely unaltered during a chemical reaction. The model first predicts the set
of graph edits transforming the target into incomplete molecules called
synthons. Next, the model learns to expand synthons into complete molecules by
attaching relevant leaving groups. This decomposition simplifies the
architecture, making its predictions more interpretable, and also amenable to
manual correction. Our model achieves a top-1 accuracy of ,
outperforming previous template-free and semi-template-based methods
A Rapid Cloning Method Employing Orthogonal End Protection
We describe a novel in vitro cloning strategy that combines standard tools in molecular biology with a basic protecting group concept to create a versatile framework for the rapid and seamless assembly of modular DNA building blocks into functional open reading frames. Analogous to chemical synthesis strategies, our assembly design yields idempotent composite synthons amenable to iterative and recursive split-and-pool reaction cycles. As an example, we illustrate the simplicity, versatility and efficiency of the approach by constructing an open reading frame composed of tandem arrays of a human fibronectin type III (FNIII) domain and the von Willebrand Factor A2 domain (VWFA2), as well as chimeric (FNIII)n-VWFA2-(FNIII)n constructs. Although we primarily designed this strategy to accelerate assembly of repetitive constructs for single-molecule force spectroscopy, we anticipate that this approach is equally applicable to the reconstitution and modification of complex modular sequences including structural and functional analysis of multi-domain proteins, synthetic biology or the modular construction of episomal vectors
Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products
Puupehenones have been isolated from the marine sponge Chondrosia chucalla, which belong to a growing family of natural products with more than 100 members. These marine natural products have attracted increasing attention mainly due to their wide variety of biological activities such as antitumor, antiviral, and anti-HIV, and thus offer promising opportunities for new drug development. This chapter covers the approaches to the total synthesis of puupehenone-type marine natural products including puupehenol, puupehenone, puupehedione, and halopuupehenones. The routes begin with the construction of their basic skeletons, followed by the modification of their C- and D-rings. The contents are divided into two sections in terms of the key strategies employed to construct the basic skeleton. One is the convergent synthesis route with two synthons coupled by nucleophilic or electrophilic reaction, and the other is the linear synthesis route with polyene series cyclization as a key reaction
Recent Developments in Structure-Based Virtual Screening Approaches
Drug development is a wide scientific field that faces many challenges these
days. Among them are extremely high development costs, long development times,
as well as a low number of new drugs that are approved each year. To solve
these problems, new and innovate technologies are needed that make the drug
discovery process of small-molecules more time and cost-efficient, and which
allow to target previously undruggable target classes such as protein-protein
interactions. Structure-based virtual screenings have become a leading
contender in this context. In this review, we give an introduction to the
foundations of structure-based virtual screenings, and survey their progress in
the past few years. We outline key principles, recent success stories, new
methods, available software, and promising future research directions. Virtual
screenings have an enormous potential for the development of new small-molecule
drugs, and are already starting to transform early-stage drug discovery.Comment: 22 pages, 2 figure
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Ruthenium(II)-bis(4'-(4-ethynylphenyl)-2,2':6', 2''-terpyridine) - A versatile synthon in supramolecular chemistry. Synthesis and characterization
A homoleptic ethynyl-substituted ruthenium(II)-bisterpyridine complex representing a versatile synthon in supramolecular chemistry was synthesized and analyzed by NMR spectroscopy, mass spectrometry and X-ray diffractometry. Furthermore, its photophysical properties were detailed by UV/Vis absorption, emission and resonance Raman spectroscopy. In order to place the results obtained in the context of the vast family of ruthenium coordination compounds, two structurally related complexes were investigated accordingly. These reference compounds bear either no or an increased chromophore in the 4Ì€-position. The spectroscopic investigations reveal a systematic bathochromic shift of the absorption and emission maximum upon increasing chromophore size. This bathochromic shift of the steady state spectra occurs hand in hand with increasing resonance Raman intensities upon excitation of the metal-to-ligand charge-transfer transition. The latter feature is accompanied by an increased excitation delocalization over the chromophore in the 4Ì€-position of the terpyridine. Thus, the results presented allow for a detailed investigation of the electronic effects of the ethynyl substituent on the metal-to-ligand charge-transfer states in the synthon for click reactions leading to coordination polymers
Synthesis and applications of theranostic oligonucleotides carrying multiple fluorine atoms
The use of various oligonucleotide (ON) syntheses and post-synthetic strategies for targeted chemical modification enables improving their efficacy as potent modulators of gene expression levels in eukaryotic cells. However, the search still continues for new approaches designed for increasing internalization, lysosomal escape, and tissue specific delivery of ON. In this review we emphasized all aspects related to the synthesis and properties of ON derivatives carrying multifluorinated (MF) groups. These MF groups have unique physico-chemical properties because of their simultaneous hydrophobicity and lipophobicity. Such unusual combination of properties results in the overall modification of ON mode of interaction with the cells and making multi-fluorination highly relevant to the goal of improving potency of ON as components of new therapies. The accumulated evidence so far is pointing to high potential of ON probes, RNAi components and ON imaging beacons carrying single or multiple MF groups for improving the stability, specificity of interaction with biological targets and delivery of ONs in vitro and potentially in vivo
An efficient graph generative model for navigating ultra-large combinatorial synthesis libraries
Virtual, make-on-demand chemical libraries have transformed early-stage drug
discovery by unlocking vast, synthetically accessible regions of chemical
space. Recent years have witnessed rapid growth in these libraries from
millions to trillions of compounds, hiding undiscovered, potent hits for a
variety of therapeutic targets. However, they are quickly approaching a size
beyond that which permits explicit enumeration, presenting new challenges for
virtual screening. To overcome these challenges, we propose the Combinatorial
Synthesis Library Variational Auto-Encoder (CSLVAE). The proposed generative
model represents such libraries as a differentiable, hierarchically-organized
database. Given a compound from the library, the molecular encoder constructs a
query for retrieval, which is utilized by the molecular decoder to reconstruct
the compound by first decoding its chemical reaction and subsequently decoding
its reactants. Our design minimizes autoregression in the decoder, facilitating
the generation of large, valid molecular graphs. Our method performs fast and
parallel batch inference for ultra-large synthesis libraries, enabling a number
of important applications in early-stage drug discovery. Compounds proposed by
our method are guaranteed to be in the library, and thus synthetically and
cost-effectively accessible. Importantly, CSLVAE can encode out-of-library
compounds and search for in-library analogues. In experiments, we demonstrate
the capabilities of the proposed method in the navigation of massive
combinatorial synthesis libraries.Comment: 36th Conference on Neural Information Processing Systems (NeurIPS
2022
RLSynC: Offline-Online Reinforcement Learning for Synthon Completion
Retrosynthesis is the process of determining the set of reactant molecules
that can react to form a desired product. Semi-template-based retrosynthesis
methods, which imitate the reverse logic of synthesis reactions, first predict
the reaction centers in the products, and then complete the resulting synthons
back into reactants. These methods enable necessary interpretability and high
practical utility to inform synthesis planning. We develop a new offline-online
reinforcement learning method RLSynC for synthon completion in
semi-template-based methods. RLSynC assigns one agent to each synthon, all of
which complete the synthons by conducting actions step by step in a
synchronized fashion. RLSynC learns the policy from both offline training
episodes and online interactions which allow RLSynC to explore new reaction
spaces. RLSynC uses a forward synthesis model to evaluate the likelihood of the
predicted reactants in synthesizing a product, and thus guides the action
search. We compare RLSynC with the state-of-the-art retrosynthesis methods. Our
experimental results demonstrate that RLSynC can outperform these methods with
improvement as high as 14.9% on synthon completion, and 14.0% on
retrosynthesis, highlighting its potential in synthesis planning.Comment: 11 pages, 8 figures, 6 table
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