Browse
Submit Data
Databases
API
Help

Dataset Information

11 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A small-molecule chemical interface for molecular programs.

ABSTRACT: In vitro molecular circuits, based on DNA-programmable chemistries, can perform an increasing range of high-level functions, such as molecular level computation, image or chemical pattern recognition and pattern generation. Most reported demonstrations, however, can only accept nucleic acids as input signals. Real-world applications of these programmable chemistries critically depend on strategies to interface them with a variety of non-DNA inputs, in particular small biologically relevant chemicals. We introduce here a general strategy to interface DNA-based circuits with non-DNA signals, based on input-translating modules. These translating modules contain a DNA response part and an allosteric protein sensing part, and use a simple design that renders them fully tunable and modular. They can be repurposed to either transmit or invert the response associated with the presence of a given input. By combining these translating-modules with robust and leak-free amplification motifs, we build sensing circuits that provide a fluorescent quantitative time-response to the concentration of their small-molecule input, with good specificity and sensitivity. The programmability of the DNA layer can be leveraged to perform DNA based signal processing operations, which we demonstrate here with logical inversion, signal modulation and a classification task on two inputs. The DNA circuits are also compatible with standard biochemical conditions, and we show the one-pot detection of an enzyme through its native metabolic activity. We anticipate that this sensitive small-molecule-to-DNA conversion strategy will play a critical role in the future applications of molecular-level circuitry.

SUBMITTER: Shenshin VA

PROVIDER: S-EPMC8287923 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.

Project description:There is growing interest in the use of structure-based virtual screening to identify small molecules that inhibit challenging protein-protein interactions (PPIs). In this study, we investigated how effectively chemical library members docked at the PPI interface mimic the position of critical side-chain residues known as "hot spots". Three compound collections were considered, a commercially available screening collection (ChemDiv), a collection of diversity-oriented synthesis (DOS) compounds that contains natural-product-like small molecules, and a library constructed using established reactions (the "screenable chemical universe based on intuitive data organization", SCUBIDOO). Three different tight PPIs for which hot-spot residues have been identified were selected for analysis: uPAR⋅uPA, TEAD4⋅Yap1, and CaV α⋅CaV β. Analysis of library physicochemical properties was followed by docking to the PPI receptors. A pharmacophore method was used to measure overlap between small-molecule substituents and hot-spot side chains. Fragment-like conformationally restricted small molecules showed better hot-spot overlap for interfaces with well-defined pockets such as uPAR⋅uPA, whereas better overlap was observed for more complex DOS compounds in interfaces lacking a well-defined binding site such as TEAD4⋅Yap1. Virtual screening of conformationally restricted compounds targeting uPAR⋅uPA and TEAD4⋅Yap1 followed by experimental validation reinforce these findings, as the best hits were fragment-like and had few rotatable bonds for the former, while no hits were identified for the latter. Overall, such studies provide a framework for understanding PPIs in the context of additional chemical matter and new PPI definitions.

| S-EPMC7175409 | biostudies-literature

SPLINTS: small-molecule protein ligand interface stabilizers.

Project description:Regulatory protein-protein interactions are ubiquitous in biology, and small molecule protein-protein interaction inhibitors are an important focus in drug discovery. Remarkably little attention has been given to the opposite strategy-stabilization of protein-protein interactions, despite the fact that several well-known therapeutics act through this mechanism. From a structural perspective, we consider representative examples of small molecules that induce or stabilize the association of protein domains to inhibit, or alter, signaling for nuclear hormone, GTPase, kinase, phosphatase, and ubiquitin ligase pathways. These SPLINTS (small-molecule protein ligand interface stabilizers) drive interactions that are in some cases physiologically relevant, and in others entirely adventitious. The diverse structural mechanisms employed suggest approaches for a broader and systematic search for such compounds in drug discovery.

| S-EPMC4834252 | biostudies-literature

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.

Project description:Zinc-finger ubiquitin-binding domains (ZnF-UBDs) are noncatalytic domains mostly found in deubiquitylases (DUBs) such as USP3. They represent an underexplored opportunity for the development of deubiquitylase-targeting chimeras (DUBTACs) to pharmacologically induce the deubiquitylation of target proteins. We previously showed that ZnF-UBDs are ligandable domains. Here, a focused small molecule library screen against a panel of 11 ZnF-UBDs led to the identification of compound 59, a ligand engaging the ZnF-UBD of USP3 with a KD of 14 μM. The compound binds the expected C-terminal ubiquitin binding pocket of USP3 as shown by hydrogen-deuterium exchange mass spectrometry experiments and does not inhibit the cleavage of K48-linked diubiquitin by USP3. As such, this molecule is a chemical starting point toward chemical tools that could be used to interrogate the function of the USP3 Znf-UBD and the consequences of recruiting USP3 to ubiquitylated proteins.

| S-EPMC10785082 | biostudies-literature

Small Molecule Probes That Perturb A Protein-protein Interface In Antithrombin.

Project description:Small molecule probes for perturbing protein-protein interactions (PPIs) in vitro can be useful if they cause the target proteins to undergo biomedically relevant changes to their tertiary and quaternary structures. Application of the Exploring Key Orientations (EKO) strategy (J. Am. Chem. Soc., 2013, 135, 167 - 173) to a piperidinone-piperidine chemotype 1 indicated specific derivatives were candidates to perturb a protein-protein interface in the α-antithrombin dimer; those particular derivatives of 1 were prepared and tested. In the event, most of them significantly accelerated oligomerization of monomeric α-antithrombin, which is metastable in its oligomeric state. This assertion is supported by data from gel electrophoresis (non-denaturing PAGE; throughout) and probe-induced loss of α-antithrombin's inhibitor activity in a reaction catalyzed by thrombin. Kinetics of α-antithrombin oligomerization induced by the target compounds were examined. It was found that probes with O-benzyl-protected serine side-chains are the most active catalysts in the series, and reasons for this, based on modeling experiments, are proposed. Overall, this study reveals one of the first examples of small molecules designed to act at a protein-protein interface relevant to oligomerization of a serpin (ie α-antithrombin). The relevance of this to formation of oligomeric serpin fibrils, associated with the disease states known as "serpinopathies", is discussed.

| S-EPMC4226170 | biostudies-literature

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling.

Project description:The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM-44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.

| S-EPMC7927014 | biostudies-literature

In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface.

Project description:Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α') subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein-protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way.

| S-EPMC5374420 | biostudies-literature

Small-Molecule Intervention At The Dimerization Interface Of Survivin By Novel Rigidized Scaffolds.

Project description:IntroductionSurvivin is a nodal protein involved in several cellular pathways. It is a member of the IAP family and an integral component of the chromosomal passenger complex, where it binds to borealin and INCENP through its dimerization interface. By targeting survivin with a small molecule at its dimerization interface, inhibition of the proliferation of cancer cells has been suggested. With Abbott 8, a small-molecule dimerization inhibitor has been recently reported. The structure-activity relationship of this series of inhibitors implied that the middle pyridin-2(1H)-one ring did not tolerate modifications of any kind.MethodsBased on the synthetic strategy of Abbott 8 using multicomponent reactions, we synthesized a series of small molecules bearing a novel rigidized core scaffold. This rigidization strategy was accomplished by integrating the pyridin-2(1H)-one and its 6-phenyl substituent into a tricyclic structure, linking position 5 of pyridin-2(1H)-one to the phenyl substituent by rings of different sizes. The new scaffolds were designed based on in silico molecular dynamics of survivin.ResultsBinding of these rigidized scaffolds to the recombinant L54M mutant of survivin was evaluated, revealing affinities in the low micromolar range.ConclusionThis easily accessible, new class of survivin-dimerization modulators is an interesting starting point for further lead optimization.

| S-EPMC6927794 | biostudies-literature

Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface.

Project description:We recently identified AG1, a small-molecule activator that functions by promoting oligomerization of glucose-6-phosphate dehydrogenase (G6PD) to the catalytically competent forms. Biochemical experiments indicate that the activation of G6PD by the original hit molecule (AG1) is noncovalent and that one C2 -symmetric region of the G6PD homodimer is important for ligand function. Consequently, the disulfide in AG1 is not required for activation of G6PD, and a number of analogues were prepared without this reactive moiety. Our study supports a mechanism of action whereby AG1 bridges the dimer interface at the structural nicotinamide adenine dinucleotide phosphate (NADP+ ) binding sites of two interacting G6PD monomers. Small molecules that promote G6PD oligomerization have the potential to provide a first-in-class treatment for G6PD deficiency. This general strategy could be applied to other enzyme deficiencies in which control of oligomerization can enhance enzymatic activity and/or stability.

| S-EPMC6701841 | biostudies-literature

Chemical 'Jekyll and Hyde's: small-molecule inhibitors of developmental signaling pathways.

Project description:Small molecules that perturb developmental signaling pathways can have devastating effects on embryonic patterning, as evidenced by the chemically induced onset of cyclopic lambs and children with severely shortened limbs during the 1950s. Recent studies, however, have revealed critical roles for these pathways in human disorders and diseases, spurring the re-examination of these compounds as new targeted therapies. In this tutorial review, we describe four case studies of teratogenic compounds, including inhibitors of the Hedgehog (Hh), Wnt, and bone morphogenetic protein (BMP) pathways. We discuss how these teratogens were discovered, their mechanisms of action, their utility as molecular probes, and their potential as therapeutic agents. We also consider current challenges in the field and possible directions for future research.

| S-EPMC3137710 | biostudies-literature

Interface Tuning between Two Connecting Bulk Heterojunctions in Small Molecule Bilayer Ternary Solar Cells.

Project description:Bilayer ternary solar cells are a kind of novel organic photovoltaic device with a triple-component active layer but are different from the ternary bulk heterojunction (BHJ) blend. Two binary BHJs with a common acceptor (or donor) are deposited sequentially in this kind of device. Here, we study the fabrication and optimization of bilayer ternary solar cells using metal phthalocyanine donors and fullerene acceptor. The device power conversion efficiency (PCE) shows a significant dependence on the interface between the two binary BHJs. The interface formed by stacking two BHJs directly demonstrates severe restrictions on the device efficiency. We find that the photovoltaic performance of bilayer ternary cells can be improved by inserting a C60 molecular monolayer between the two binary BHJs. The effect of the C60 interfacial layer on charge transport is analyzed based on their transport characteristics under negative bias. A relationship between the C60 interfacial layer and recombination under illumination is discussed. This work reveals a particular influence due to the interface facing three materials in organic solar cells.

| S-EPMC7663015 | 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