Target Discovery Driven by Chemical Biology and Computational Biology

The Chemical Record, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Target identification is crucial for drug screening and development because it can reveal the mechanism of action ensure reliability accuracy results. Chemical biology, an interdisciplinary field combining chemistry assist in this process by studying interactions between active molecular compounds proteins their physiological effects. It also help predict potential targets or candidates, develop new biomarker assays diagnostic reagents, evaluate selectivity range to reduce risk off-target biology achieve these goals using techniques such as changing protein thermal stability, enzyme sensitivity, structure applying probes, isotope labeling mass spectrometry. Concurrently, computational employs a diverse array models targets. This approach offers innovative avenues repurposing existing drugs. In paper, we review reported chemical identifying different types that provide valuable insights target discovery.

Language: Английский

---

An Integrated Strategy for Deciphering the Action Mechanism of Emplastrum: Prescription Analysis- Component Identification- Virtual Screening and Affinity Testing in the Case of Yaoshen Gao

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 119369 - 119369

Published: Jan. 1, 2025

Language: Английский

---

Differential scanning fluorimetry followed by microscale thermophoresis and/or isothermal titration calorimetry as an efficient tool for ligand screening

Biophysical Reviews, Journal Year: 2025, Volume and Issue: 17(1), P. 199 - 223

Published: Feb. 1, 2025

Various biophysical and biochemical techniques have been developed to measure the affinity of interacting molecules. This review analyzes combination three methods: differential scanning fluorimetry as initial high-throughput screening technique microscale thermophoresis isothermal titration calorimetry complementary methods quantify binding affinity. The presented work is first detailed compare strengths flaws these specific methods, well their application possibilities complementarity. fundamentals will be covered, including most often-used models for characterizing observable phenomena an emphasis on analyzing data. A comprehensive numerous approaches data analysis found in literature additionally provided, with benefits drawbacks each, pitfalls related concerns. Finally, examples different systems presented, used some discrepancies results described discussed.

Language: Английский

---

Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening

Atherosclerosis, Journal Year: 2025, Volume and Issue: unknown, P. 119174 - 119174

Published: March 1, 2025

An elevated level of lipoprotein(a), or Lp(a), in the bloodstream has been causally linked to development atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Steady state levels circulating lipoproteins are modulated by their rate clearance, but identity Lp(a) uptake receptor(s) controversial. We performed a genome-scale CRISPR screen functionally interrogate all potential regulators HuH7 cells. Screen validation was single gene disruption overexpression. Direct binding between purified recombinant protein tested using biolayer interferometry. association human genetic variants analyzed UK Biobank cohort. The top positive negative our were LDLR MYLIP, encoding LDL receptor its ubiquitin ligase IDOL, respectively. also found significant correlation for other genes with established roles regulation. No products, including those previously proposed as receptors, exhibited effect on screen. validated functional influence expression uptake, confirmed vitro extracellular domain detected an loss-of-function increased Our findings support central role mediating hepatocytes.

Language: Английский

---

Maximizing the Accuracy of Equilibrium Dissociation Constants for Affinity Complexes: From Theory to Practical Recommendations

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(9), P. 1852 - 1867

Published: Aug. 9, 2024

The equilibrium dissociation constant (

Language: Английский

---

Multiplexed Bio‐detection on an Interferometric Optical Waveguide Assembly

Advanced Materials Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Multiplexed remote bio‐detection is demonstrated through an optical waveguide assembly coated with interferometric layers. Image conduits (IC)s, composed of 3012 individual cores, are layers tantalum pentoxide (Ta 2 O 5 ) and silica (SiO to transform each core into a sensitive sensor. The spectral response the IC as function refractive index (RI) changes obtained compared simulated one. experimental sensitivities resolutions cores assessed in detection mode by imaging assembly. For 75% sensitivity better than 510%. RIU −1 (RI Unit) obtained, corresponding resolution 7 × 10 −4 RIU. Furthermore, face functionalized two localized arrays hundred‐micrometer droplets containing different oligonucleotide (ODN) probes using polymeric 3D‐printed microcantilever. Hybridization complementary ODN strands detected for one probes, second being negative control. Interaction kinetics monitored areas grouping several or on cores. Thus, multiplexed surface first time paving way applications multiplex situ biosensing, and, ultimately, vivo endoscopic diagnosis.

Language: Английский

---

Focal Molography Allows for Affinity and Concentration Measurements of Proteins in Complex Matrices with High Accuracy

Biosensors, Journal Year: 2025, Volume and Issue: 15(2), P. 66 - 66

Published: Jan. 22, 2025

Characterizing biomolecular receptor–ligand interactions is critical for research and development. However, performing analyses in complex, biologically relevant matrices, such as serum, remains challenging due to non-specific binding that often impairs measurements. Here, we evaluated Focal Molography (FM) determining KD kinetic constants comparison gold-standard methods using single-domain heavy-chain antibodies various systems. FM provided highly comparable SPR BLI standard buffers containing blocking proteins, with KDs of soluble CD4 (sCD4) within a 2.4-fold range across technologies. In lacking demonstrated greater robustness against rebinding effects. exhibited stable baseline signals, unlike BLI, yielded sCD4 interaction 50% Bovine Serum 1.8-fold those obtained buffers. For molecules prone (Granzyme B), successfully determined without external referencing. Finally, enabled direct analyte quantification complex matrices. cell culture media FBS showed recovery rates 97.8–100.3% an inter-assay CV below 1.3%. This study demonstrates the high potential affinity determination biomarker enabling reliable measurements under conditions.

Language: Английский

---

A Review on Perception of Binding Kinetics in Affinity Biosensors: Challenges and Opportunities

ACS Omega, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

There are challenges associated with design and development of affinity biosensors due to the complicated multiphysics nature system. Understanding binding interaction between target molecules immobilized receptors its kinetics is a crucial step develop robust reliable biosensor technologies. Evaluation in becomes more important challenging for clinical samples complex matrix. Despite drastic advancements technologies, having practical perception has remained critical bottleneck limited fundamental understanding. This Review aims provide comprehensive discussion on concepts advances developed so far biosensors. Here, modeling approaches measurement techniques presented characterize interactions while effect fouling secondary factors will be discussed concept kinetics. investigate existing research gaps potential opportunities

Language: Английский

---

Tuning TCR complex recruitment to the T cell antigen coupler (TAC) enhances TAC-T cell function

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 25, 2025

The T cell antigen coupler (TAC) receptor is a novel synthetic designed to maximize the therapeutic potential of cells in absence tonic signaling or receptor-related toxicities. Prior studies indicated that TACs provide safe and long-lasting anti-tumor immunity multiple preclinical models solid tumors supported by mounting clinical evidence. TAC receptors function targeting cancer associated surface while recapitulating natural (TCR) signaling, which involves both TCR/CD3 recruitment intracellular CD4 co-receptor activity. While other designs exist redirect TCR towards antigens, technology unique binding distinctly separated from complex recruitment. In present study, we show single amino-acid changes domain responsible for Claudin 18.2-directed led enhanced vivo functionality. Analyzing biophysical properties suggests with high affinities are suboptimal compared constructs lower notably fast off-rates. This work demonstrates balancing critical when designing effective receptors, concept may apply more broadly approaches relying on signaling.

Language: Английский

---

FAP inhibitors: are we really using the best method to evaluate the residence time?

European Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Language: Английский

---