Synthetically Accessible Virtual Inventory (SAVI)

Abstract We have made available a database of over 1 billion compounds predicted to be easily synthesizable, called Synthetically Accessible Virtual Inventory (SAVI). They have been created by a set of transforms based on an adaptation and extension of the CHMTRN/PATRAN programming languages describing chemical synthesis expert knowledge, which originally stem from the LHASA project. The chemoinformatics toolkit CACTVS was used to apply a total of 53 transforms to about 150,000 readily available building blocks (enamine.net). Only single-step, two-reactant syntheses were calculated for this database even though the technology can execute multi-step reactions. The possibility to incorporate scoring systems in CHMTRN allowed us to subdivide the database of 1.75 billion compounds in sets according to their predicted synthesizability, with the most-synthesizable class comprising 1.09 billion synthetic products. Properties calculated for all SAVI products show that the database should be well-suited for drug discovery. It is being made publicly available for free download from https://doi.org/10.35115/37n9-5738.

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Synthetically Accessible Virtual Inventory (SAVI)

10.26434/chemrxiv.12185559.v1 ◽

2020 ◽

Author(s):

Hitesh Patel ◽

Wolf Ihlenfeldt ◽

Philip Judson ◽

Yurii S. Moroz ◽

Yuri Pevzner ◽

...

Keyword(s):

Drug Discovery ◽

Chemical Synthesis ◽

Programming Languages ◽

Expert Knowledge ◽

Scoring Systems ◽

Building Blocks ◽

Single Step

We have made available a database of over 1 billion compounds predicted to be easily synthesizable. They have been created by a set of transforms based on an adaptation and extension of the CHMTRN/PATRAN programming languages describing chemical synthesis expert knowledge, which originally stem from the LHASA project. The chemoinformatics toolkit CACTVS was used to apply a total of 53 transforms to about 150,000 readily available building blocks (enamine.net). Only single-step, two-reactant syntheses were calculated for this database even though the technology can execute multi-step reactions. The possibility to incorporate scoring systems in CHMTRN allowed us to subdivide the database of 1.75 billion compounds in sets according to their predicted synthesizability, with the most-synthesizable class comprising 1.09 billion synthetic products. Properties calculated for all SAVI products show that the database should be well-suited for drug discovery. It is being made publicly available for free download from https://cactus.nci.nih.gov/download/savi_download/.

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Development of Strategies for Glycopeptide Synthesis: An Overview on the Glycosidic Linkage

Current Organic Chemistry ◽

10.2174/1385272824999200701121037 ◽

2020 ◽

Vol 24 (21) ◽

pp. 2475-2497

Author(s):

Andrea Verónica Rodríguez-Mayor ◽

German Jesid Peralta-Camacho ◽

Karen Johanna Cárdenas-Martínez ◽

Javier Eduardo García-Castañeda

Keyword(s):

Chemical Synthesis ◽

Solid Phase ◽

Building Blocks ◽

Heterogeneous Environments ◽

Phase Synthesis ◽

Low Concentrations ◽

Biological Sources ◽

Synthetic Routes ◽

The Impact ◽

Potential Use

Glycoproteins and glycopeptides are an interesting focus of research, because of their potential use as therapeutic agents, since they are related to carbohydrate-carbohydrate, carbohydrate-protein, and carbohydrate-lipid interactions, which are commonly involved in biological processes. It has been established that natural glycoconjugates could be an important source of templates for the design and development of molecules with therapeutic applications. However, isolating large quantities of glycoconjugates from biological sources with the required purity is extremely complex, because these molecules are found in heterogeneous environments and in very low concentrations. As an alternative to solving this problem, the chemical synthesis of glycoconjugates has been developed. In this context, several methods for the synthesis of glycopeptides in solution and/or solid-phase have been reported. In most of these methods, glycosylated amino acid derivatives are used as building blocks for both solution and solid-phase synthesis. The synthetic viability of glycoconjugates is a critical parameter for allowing their use as drugs to mitigate the impact of microbial resistance and/or cancer. However, the chemical synthesis of glycoconjugates is a challenge, because these molecules possess multiple reaction sites and have a very specific stereochemistry. Therefore, it is necessary to design and implement synthetic routes, which may involve various protection schemes but can be stereoselective, environmentally friendly, and high-yielding. This review focuses on glycopeptide synthesis by recapitulating the progress made over the last 15 years.

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Trying to Professionalize Expert Knowledge (Part I): The Short Life of the Municipal Administration Service, 1926-1933

Public Voices ◽

10.22140/pv.525 ◽

2017 ◽

Vol 15 (1) ◽

pp. 9 ◽

Cited By ~ 1

Author(s):

Mordecai Lee

Keyword(s):

Best Practices ◽

Public Administration ◽

Expert Knowledge ◽

Building Blocks ◽

Early History ◽

Short Life ◽

Organizational History ◽

Municipal Administration ◽

History Of ◽

Wide Dissemination

One of the building blocks of the professionalization of American public administration was the recognition of the need for expert knowledge and the wide dissemination of that information to practitioners. Municipal civil servants could adopt and adapt these best practices in their localities. Such was the purpose of the Municipal Administration Service (1926-1933), initially founded by the National Municipal League and funded by the Rockefeller philanthropies. This article is an organizational history of the Service. It presents the life cycle of the agency, including its operations, funding, problems, and the behind-the-scenes public administration politics which led to its demise. In all, the Municipal Administration Service captures the early history of American public administration, its attempt to demonstrate that it was a full-fledged profession with recognized experts and managerial advice that ultimately proved unable to perpetuate itself.

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Synthesis of sp3-Enriched β-Fluoro Sulfonyl Chlorides

Synthesis ◽

10.1055/s-0040-1706101 ◽

2020 ◽

Author(s):

Oleksandr O. Grygorenko ◽

Rustam Gurbanov ◽

Andriy Sokolov ◽

Sergey Golovach ◽

Kostiantyn Melnykov ◽

...

Keyword(s):

Drug Discovery ◽

Double Bond ◽

Building Blocks ◽

Protecting Groups ◽

Sulfonyl Chlorides ◽

Wide Range ◽

Cyclic Compounds

AbstractA three-step approach to the synthesis of sp3-enriched β-fluoro sulfonyl chlorides starting from alkenes is reported. The method was successfully applied to a wide range of acyclic and cyclic substrates, bearing either an exocyclic or an endocyclic double bond. The procedure worked with a wide range of substrates and tolerated a number of functional and protecting groups. Moreover, the target cyclic compounds were obtained as single cis diastereomers on a multigram scale. The title compounds are promising building blocks for drug discovery that can be used to obtain sp3-enriched β-fluoro and α,β-unsaturated sulfonamides.

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A Straightforward Methodology to Overcome Solubility Challenges for N-Terminal Cysteinyl Peptide Segments Used in Native Chemical Ligation

10.26434/chemrxiv.13174922 ◽

2020 ◽

Author(s):

Skander Abboud ◽

El hadji Cisse ◽

Michel Doudeau ◽

Hélène Bénédetti ◽

Vincent AUCAGNE

Keyword(s):

Amino Acids ◽

Chemical Synthesis ◽

Building Blocks ◽

Native Chemical Ligation ◽

Synthetic Approach ◽

Chemical Ligation ◽

Limited Solubility ◽

Peptide Segments

One of the main limitations encountered during the chemical synthesis of proteins through native chemical ligation (NCL) is the limited solubility of some of the peptide segments. The most commonly used solution to overcome this problem is to derivatize the segment with a temporary solubilizing tag. Conveniently, the tag can be introduced on the thioester segment in such a way that it is removed concomitantly with the NCL reaction. We herein describe a generalization of this approach to N-terminal cysteinyl segment counterparts, using a straightforward synthetic approach that can be easily automated from commercially available building blocks, and applied it to a well-known problematic target, SUMO-2 (93 amino acids).

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Robust, Efficient and Automated Methods for Accurate Prediction of Protein-Ligand Binding Affinities in AMBER Drug Discovery Boost

10.26434/chemrxiv.14727573 ◽

2021 ◽

Author(s):

Tai-Sung Lee ◽

Hsu-Chun Tsai ◽

Abir Ganguly ◽

Timothy J Giese ◽

Darrin M. York

Keyword(s):

Drug Discovery ◽

Ligand Binding ◽

Binding Affinity ◽

Single Step ◽

Simulation Software ◽

Rational Drug Design ◽

Computer Hardware ◽

Binding Affinities ◽

Methodology Development ◽

Industry Applications

Recent concurrent advances in methodology development, computer hardware and simulation software has transformed our ability to make practical, quantitative predictions of relative ligand binding affinities to guide rational drug design. In the past, these calculations have been hampered by the lack of affordable software with highly efficient implementations of state-of-the-art methods on specialized hardware such as graphical processing units, combined with the paucity of available workflows to streamline throughput for real-world industry applications. Herein we discuss recent methodology development, GPU-accelerated implementation, and workflow creation for alchemical free energy simulation methods in the AMBER Drug Discovery Boost (AMBER-DD Boost) package available as a patch to AMBER20. Among the methodological advances are 1) new methods for the treatment of softcore potentials that overcome long standing end-point catastrophe and softcore imbalance problems and enable single-step alchemical transformations between ligands, and 2) new adaptive enhanced sampling methods in the "alchemical" (or "λ") dimension to accelerate convergence and obtain high precision ligand binding affinity predictions, 3) robust network-wide analysis methods that include cycle closure and reference constraints and restraints, and 4) practical workflows that enable streamlined calculations on large datasets to be performed. Benchmark calculations on various systems demonstrate that these tools deliver an outstanding combination of accuracy and performance, resulting in reliable high-throughput binding affinity predictions at affordable cost.<br>

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Cover Feature: Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery (Chem. Eur. J. 47/2018)

Chemistry - A European Journal ◽

10.1002/chem.201802504 ◽

2018 ◽

Vol 24 (47) ◽

pp. 12102-12102

Author(s):

Roman M. Bychek ◽

Vadym V. Levterov ◽

Iryna V. Sadkova ◽

Andrey A. Tolmachev ◽

Pavel K. Mykhailiuk

Keyword(s):

Drug Discovery ◽

Building Blocks

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Exploring Low-Carbon Futures: A Web Service Approach to Linking Diverse Climate-Energy-Economy Models

Energies ◽

10.3390/en12152880 ◽

2019 ◽

Vol 12 (15) ◽

pp. 2880 ◽

Cited By ~ 4

Author(s):

Getachew F. Belete ◽

Alexey Voinov ◽

Iñaki Arto ◽

Kishore Dhavala ◽

Tatyana Bulavskaya ◽

...

Keyword(s):

Web Service ◽

Programming Languages ◽

Computable General Equilibrium ◽

Spatial Scales ◽

Simulation Models ◽

Building Blocks ◽

Integrated Assessment Model ◽

Assessment Model ◽

Low Carbon ◽

Mitigation And Adaptation

The use of simulation models is essential when exploring transitions to low-carbon futures and climate change mitigation and adaptation policies. There are many models developed to understand socio-environmental processes and interactions, and analyze alternative scenarios, but hardly one single model can serve all the needs. There is much expectation in climate-energy research that constructing new purposeful models out of existing models used as building blocks can meet particular needs of research and policy analysis. Integration of existing models, however, implies sophisticated coordination of inputs and outputs across different scales, definitions, data and software. This paper presents an online integration platform which links various independent models to enhance their scope and functionality. We illustrate the functionality of this web platform using several simulation models developed as standalone tools for analyzing energy, climate and economy dynamics. The models differ in levels of complexity, assumptions, modeling paradigms and programming languages, and operate at different temporal and spatial scales, from individual to global. To illustrate the integration process and the internal details of our integration framework we link an Integrated Assessment Model (GCAM), a Computable General Equilibrium model (EXIOMOD), and an Agent Based Model (BENCH). This toolkit is generic for similar integrated modeling studies. It still requires extensive pre-integration assessment to identify the ‘appropriate’ models and links between them. After that, using the web service approach we can streamline module coupling, enabling interoperability between different systems and providing open access to information for a wider community of users.

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Glycosylated α-Azido Amino Acids: Versatile Intermediates in the Synthesis of Neoglycoconjugates

Synlett ◽

10.1055/s-0036-1591902 ◽

2018 ◽

Vol 29 (07) ◽

pp. 904-907 ◽

Cited By ~ 2

Author(s):

Trinidad Velasco-Torrijos ◽

Róisín O’Flaherty

Keyword(s):

Amino Acids ◽

Drug Discovery ◽

Building Blocks ◽

Sensor Development ◽

Galactosyl Ceramide

A series of glycosylated α-azido amino acids was synthesized as precursors for neoglycoconjugates, a class of important biomolecules for drug discovery, and sensor development. The synthetically challenging 1,2-cis α-galactosylated species described herein were designed as building blocks in the synthesis of analogues of α-galactosyl ceramide, a potent immunomodulator. A benzyl-protected 1,2,3-triazolyl α-galactosyl-l-serine derivative was prepared using copper azide alkyne cycloaddition to showcase the potential of glycosylated α-azido amino acids in neoglycoconjugate design.

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