Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of a novel CCR5 antagonist lead compound through fragment assembly.

ABSTRACT: CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4-yl)piperazin-1-yl)butane-1,4-dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminary SARs were obtained, which are in good agreement with the molecular binding model and should prove helpful for future antagonist design. The novel scaffold presented here might also be useful in the development of maraviroc-derived second generation CCR5 antagonists.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6245477 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery of a novel CCR5 antagonist lead compound through fragment assembly.

Liu Yanqing Y Zhou Enkun E Yu Kunqian K Zhu Jin J Zhang Yu Y Xie Xin X Li Jian J Jiang Hualiang H

Molecules (Basel, Switzerland) 20081001 10

CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4-yl)piperazin-1-yl)butane-1,4-dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminar ...[more]

PMID: 18830165

Similar Datasets

Rapid lead discovery through iterative screening of one bead one compound libraries.

Project description:Primary hits that arise from screening one bead one compound (OBOC) libraries against a target of interest rarely have high potency. However, there has been little work focused on the development of an efficient workflow for primary hit improvement. In this study, we show that by characterizing the binding constants for all of the hits that arise from a screen, structure-activity relationship (SAR) data can be obtained to inform the design of "derivative libraries" of a primary hit that can then be screened under more demanding conditions to obtain improved compounds. Here, we demonstrate the rapid improvement of a primary hit against matrix metalloproteinase-14 using this approach.

| S-EPMC4294594 | biostudies-literature

Targeting metalloproteins by fragment-based lead discovery.

Project description:It has been estimated that nearly one-third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal-binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment-based drug discovery approach using a metal-targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target's metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics.

| S-EPMC3135788 | biostudies-literature

Anibamine, a natural product CCR5 antagonist, as a novel lead for the development of anti-prostate cancer agents.

Project description:Accumulating evidence indicates that the chemokine receptor CCR5 and the chemokine CCL5 may be involved in the proliferation and metastasis of prostate cancer. Consequently, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. As the first natural product CCR5 antagonist, anibamine provides a novel chemical structural skeleton compared with other known antagonists identified through high-throughput screening. Our studies demonstrate that anibamine produces significant inhibition of prostate cancer cell proliferation at micromolar to submicromolar concentrations as well as suppressing adhesion and invasion of the highly metastatic M12 prostate cancer cell line. Preliminary in vivo studies indicate that anibamine also inhibits prostate tumor growth in mice. These findings indicate that anibamine may prove to be a novel lead compound for the development of prostate cancer therapeutic agents.

| S-EPMC2914538 | biostudies-literature

Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist.

Project description:This report describes the discovery of a potent, orally bioavailable CC chemokine receptor 2 (CCR2) antagonist which, while optimized for CCR2 potency, also had potent CC chemokine receptor 5 (CCR5) activity.

| S-EPMC4007850 | biostudies-other

Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery.

Project description:In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hit validation by isothermal titration calorimetry and X-ray crystallography. Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors.

| S-EPMC3740835 | biostudies-literature

Process of Fragment-Based Lead Discovery-A Perspective from NMR.

Project description:Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein-protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power to probe the intrinsically weak interactions between targets and low-molecular-weight fragments. Here, we review the NMR FBLD process from initial library construction to lead generation. We describe technical aspects regarding fragment library design, ligand- and protein-observed screening, and protein-ligand structure model generation. For weak binders, the initial hit-to-lead evolution can be guided by structural information retrieved from NMR spectroscopy, including chemical shift perturbation, transferred pseudocontact shifts, and paramagnetic relaxation enhancement. This perspective examines structure-guided optimization from weak fragment screening hits to potent leads for challenging PPI targets.

| S-EPMC6273320 | biostudies-literature

An Automated Microscale Thermophoresis Screening Approach for Fragment-Based Lead Discovery.

Project description:Fragment-based lead discovery has proved to be an effective alternative to high-throughput screenings in identifying chemical matter that can be developed into robust lead compounds. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. In order to minimize the time and costs of screening, optimal combinations of biophysical techniques with maximal information content, sensitivity, and robustness are needed. Here we describe an approach utilizing automated microscale thermophoresis (MST) affinity screening to identify fragments active against MEK1 kinase. MST identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods. Furthermore, MST also provided information about ligand-induced aggregation and protein denaturation. The technique delivered a large number of binders while reducing experimentation time and sample consumption, demonstrating the potential of MST to execute and maximize the efficacy of fragment screening campaigns.

| S-EPMC4800460 | biostudies-literature

Fragment Library of Natural Products and Compound Databases for Drug Discovery.

Project description:Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.

| S-EPMC7694623 | biostudies-literature

1D NMR WaterLOGSY as an efficient method for fragment-based lead discovery.

Project description:WaterLOGSY is a sensitive ligand-observed NMR experiment for detection of interaction between a ligand and a protein and is now well-established as a screening technique for fragment-based lead discovery. Here we develop and assess a protocol to derive ligand epitope mapping from WaterLOGSY data and demonstrate its general applicability in studies of fragment-sized ligands binding to six different proteins (glycogen phosphorylase, protein peroxiredoxin 5, Bcl-xL, Mcl-1, HSP90, and human serum albumin). We compare the WaterLOGSY results to those obtained from the more widely used saturation transfer difference experiments and to the 3D structures of the complexes when available. In addition, we evaluate the impact of ligand labile protons on the WaterLOGSY data. Our results demonstrate that the WaterLOGSY experiment can be used as an additional confirmation of the binding mode of a ligand to a protein.

| S-EPMC6691826 | biostudies-literature

Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design.

Project description:Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.

| S-EPMC4309560 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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