Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Application of a sparse matrix design strategy to the synthesis of dos libraries.

ABSTRACT: We have implemented an interactive and practical sparse matrix design strategy for the synthesis of DOS libraries, which facilitates the selection of diverse library members within a user-defined range of physicochemical properties while still maintaining synthetic efficiency. The utility of this approach is illustrated with the synthesis of an 8000-membered library of stereochemically diverse medium-sized rings accessible via a build/couple/pair DOS strategy. Diverse library members were selected from a virtual library by applying the maximum dissimilarity method, while the selection of similar analogs around each diverse product was ensured by picking near neighbors algorithmically based on fingerprint comparison. Adjustable filters on compound properties, which can be tailored to suit the needs of the target biology, facilitated subset selection from the synthetically accessible compounds.

SUBMITTER: Akella LB

PROVIDER: S-EPMC3133884 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Application of a sparse matrix design strategy to the synthesis of dos libraries.

Akella Lakshmi B LB Marcaurelle Lisa A LA

ACS combinatorial science 20110428 4

We have implemented an interactive and practical sparse matrix design strategy for the synthesis of DOS libraries, which facilitates the selection of diverse library members within a user-defined range of physicochemical properties while still maintaining synthetic efficiency. The utility of this approach is illustrated with the synthesis of an 8000-membered library of stereochemically diverse medium-sized rings accessible via a build/couple/pair DOS strategy. Diverse library members were select ...[more]

PMID: 21526822

Similar Datasets

Penalized likelihood for sparse contingency tables with an application to full-length cDNA libraries.

Project description:BackgroundThe joint analysis of several categorical variables is a common task in many areas of biology, and is becoming central to systems biology investigations whose goal is to identify potentially complex interaction among variables belonging to a network. Interactions of arbitrary complexity are traditionally modeled in statistics by log-linear models. It is challenging to extend these to the high dimensional and potentially sparse data arising in computational biology. An important example, which provides the motivation for this article, is the analysis of so-called full-length cDNA libraries of alternatively spliced genes, where we investigate relationships among the presence of various exons in transcript species.ResultsWe develop methods to perform model selection and parameter estimation in log-linear models for the analysis of sparse contingency tables, to study the interaction of two or more factors. Maximum Likelihood estimation of log-linear model coefficients might not be appropriate because of the presence of zeros in the table's cells, and new methods are required. We propose a computationally efficient l1-penalization approach extending the Lasso algorithm to this context, and compare it to other procedures in a simulation study. We then illustrate these algorithms on contingency tables arising from full-length cDNA libraries.ConclusionWe propose regularization methods that can be used successfully to detect complex interaction patterns among categorical variables in a broad range of biological problems involving categorical variables.

| S-EPMC2233645 | biostudies-literature

The design and application of target-focused compound libraries.

Project description:Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries.

| S-EPMC3182092 | biostudies-literature

Diversified strategy for the synthesis of DNA-encoded oxindole libraries.

Project description:DNA-encoded library technology (DELT) employs DNA as a barcode to track the sequence of chemical reactions and enables the design and synthesis of libraries with billions of small molecules through combinatorial expansion. This powerful technology platform has been successfully demonstrated for hit identification and target validation for many types of diseases. As a highly integrated technology platform, DEL is capable of accelerating the translation of synthetic chemistry by using on-DNA compatible reactions or off-DNA scaffold synthesis. Herein, we report the development of a series of novel on-DNA transformations based on oxindole scaffolds for the design and synthesis of diversity-oriented DNA-encoded libraries for screening. Specifically, we have developed 1,3-dipolar cyclizations, cyclopropanations, ring-opening of reactions of aziridines and Claisen-Schmidt condensations to construct diverse oxindole derivatives. The majority of these transformations enable a diversity-oriented synthesis of DNA-encoded oxindole libraries which have been used in the successful hit identification for three protein targets. We have demonstrated that a diversified strategy for DEL synthesis could accelerate the application of synthetic chemistry for drug discovery.

| S-EPMC8179416 | biostudies-literature

Solid-phase synthesis of DNA-encoded libraries via an "aldehyde explosion" strategy.

Project description:We report chemistry suitable for the solid-phase synthesis of DNA-encoded libraries with an unusually high level of structural diversity. The strategy involves "exploding" an immobilized aldehyde into a plethora of different functional groups under DNA-compatible conditions.

| S-EPMC7298663 | biostudies-literature

Reagent based DOS: a "Click, Click, Cyclize" strategy to probe chemical space.

Project description:The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical-biology. Herein we report a reagent-based, diversity-oriented synthetic (DOS) strategy to probe chemical and biological space via a "Click, Click, Cyclize" protocol. In this DOS approach, three sulfonamide linchpins underwent cyclization protocols with a variety of reagents to yield a collection of structurally diverse S-heterocycles. In silico analysis is utilized to evaluate the diversity of the compound collection against chemical space (PC analysis), shape space (PMI) and polar surface area (PSA) calculations.

| S-EPMC2888000 | biostudies-literature

Gd-TEMDO: Design, Synthesis, and MRI Application.

Project description:A simple Ugi tetrazole multicomponent reaction allows the synthesis of a novel macrocyclic cyclen derivative with four appendant tetrazole arms in just two steps in excellent yields. This ligand, called TEMDO, turns out to have a high complexation affinity with lanthanoid metals. Here we describe the design, synthesis, solid-state structure, binding constant, and some MRI applications of the Gd-TEMDO complex as the first example of a congeneric family of oligo-amino tetrazoles.

| S-EPMC5363076 | biostudies-literature

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion.

Project description:Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10-14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

| S-EPMC8162264 | biostudies-literature

Sparse Covariance Matrix Estimation With Eigenvalue Constraints.

Project description:We propose a new approach for estimating high-dimensional, positive-definite covariance matrices. Our method extends the generalized thresholding operator by adding an explicit eigenvalue constraint. The estimated covariance matrix simultaneously achieves sparsity and positive definiteness. The estimator is rate optimal in the minimax sense and we develop an efficient iterative soft-thresholding and projection algorithm based on the alternating direction method of multipliers. Empirically, we conduct thorough numerical experiments on simulated datasets as well as real data examples to illustrate the usefulness of our method. Supplementary materials for the article are available online.

| S-EPMC4303596 | biostudies-literature

Diverging DOS strategy using an allene-containing tryptophan scaffold and a library design that maximizes biologically relevant chemical space while minimizing the number of compounds.

Project description:A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a microwave-assisted allenic [2 + 2] cycloaddition reaction. This same tryptophan-derived precursor afforded an indolylmethyldihydrocyclopentapyridinone 14 when subjected to a rhodium(I)-catalyzed cyclocarbonylation reaction and an indolylmethylpyrrolidinocyclopentenones 16 when reacted with molybdenum hexacarbonyl. Construction of allenic tetrahydro-?-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-?-carboline, followed by a microwave-assisted allenic [2 + 2] cycloaddition reaction, provided tetrahydrocyclobutaindoloquinolizinones 24 and the tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used as templates for the construction of a virtual library of 11?748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes. Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D) fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327,000 compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space defined by these compounds and will be synthesized and screened for biological activity.

| S-EPMC3104414 | biostudies-literature

Design, Synthesis, Investigation, and Application of a Macromolecule Photoswitch.

Project description:Azobenzene (AZO) has attracted increasing interest due to its reversible structural change upon a light stimulus. However, poor fatigue durability and the photobleaching phenomenon restricts its further application. Herein, the AZO domain as a pendent group, was incorporated into copolymers, which was synthesized by radical copolymerization in the research. Structure-properties of synthesized copolymer can be adjusted by monomer ratios. Emphatically, responsive properties of copolymer in different solutions were investigated. In the DMSO solution, copolymer exhibited effective structural change, stable rapid responsive time (1 min) upon UV light at room temperature, stable relative acceptable recovery time (100 min) upon white light at room temperature, and good fatigue resistance property. In an aqueous solution, even more controllable responsive properties and fatigue resistance properties for copolymer were verified by results. More pervasively, the recovery process could be controlled by light density and temperature. In order to clarify reasons for the difference between the AZO molecule and the AZO domain of copolymer, energy barrier or interactions between single atoms or even structural units was calculated using the density functional theory (DFT). Furthermore, the status of copolymer was characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). Finally, copolymer was further functionalized with bioactive protein (concanavalin, ConA) to reduce the cytotoxicity of the AZO molecule.

| S-EPMC6403147 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data