Design and synthesis of (E)-3-benzylideneindolin-2-one derivatives as potential allosteric inhibitors of Aurora A kinase DOI

YongLai Jiao,

Jie Zhong,

Jinfang Xu

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

The mitotic kinase Aurora A, a pivotal regulator of the cell cycle, is overexpressed in various cancers and has emerged as one most promising targets for anticancer drug discovery. However, lack specificity potential toxicity have impeded clinical trials involving orthosteric inhibitors. In this study, allosteric sites A were predicted using AlloReverse web server. Based on non-ATP competitive inhibitor Tripolin molecular docking information targeting desired site 3 series (

Language: Английский

GPCR drug discovery: new agents, targets and indications DOI
José A. Lorente, Aleksandr V. Sokolov, Gavin Ferguson

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

Citations

4
Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery DOI Creative Commons
Paolo Conflitti, Edward Lyman, Mark S.P. Sansom

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

Citations

3
Databases of ligand-binding pockets and protein-ligand interactions DOI Creative Commons
Kristy A. Carpenter, Russ B. Altman

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 1320 - 1338

Published: March 24, 2024

Many research groups and institutions have created a variety of databases curating experimental predicted data related to protein-ligand binding. The landscape available is dynamic, with new emerging established becoming defunct. Here, we review the current state that contain binding pockets interactions. We compiled list such databases, fifty-three which are currently for use. discuss variation in how defined summarize pocket-finding methods. organize into subgroups based on goals contents, describe standard use cases. also illustrate within same protein characterized differently across different databases. Finally, assess critical issues sustainability, accessibility redundancy.

Language: Английский

Citations

8
Toward the Design of Allosteric Effectors: Gaining Comprehensive Control of Drug Properties and Actions DOI Creative Commons
Wei-Ven Tee,

Sylvester Jian Ming Lim,

Igor N. Berezovsky

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

While the therapeutic potential of allosteric drugs is increasingly realized, discovery effectors largely incidental. The rational design requires new state-of-the-art approaches to account for distinct characteristics ligands and their modes action. We present a broadly applicable computational framework obtaining site-effector pairs, providing targeted, highly specific, tunable regulation any functional site. validated using main protease from SARS-CoV-2 K-Ras

Language: Английский

Citations

6
Altered zygotic gene expression caused by sperm with Tdrd6 variants disrupts early embryonic development DOI Creative Commons
Zhijie Hu, Yuqi Zhang, Renfei Cai

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(1)

Published: Jan. 1, 2025

Abstract The precise mechanisms behind early embryonic arrest due to sperm‐related factors and the most effective strategies are not yet fully understood. Here, we present two cases of male infertility linked novel TDRD6 variants, associated with oligoasthenoteratozoospermia (OAT) arrest. To investigate underlying promising therapeutic approaches, Tdrd6 knock‐in knock‐out mice were generated. variant demonstrated OAT arrest, mirroring clinical observations our patients. Sperm from both affected individuals exhibited aberrant localization phospholipase C zeta oocyte activation deficiency (OAD). application artificial (AOA) effectively overcame caused by facilitating successful pregnancies live births in human mice. Additionally, research revealed that OAD influences expression multitude genes at 2‐pronuclear (2PN) stage, Mos gene playing a pivotal role injection mRNA can mitigate this knowledge, is first study show affects 2PN stage elucidate how AOA overcomes factor‐derived enabling births.

Language: Английский

Citations

0
Allostery DOI
Mateu Montserrat‐Canals, Gabriele Cordara, Ute Krengel

et al.

Quarterly Reviews of Biophysics, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

Abstract Allostery describes the ability of biological macromolecules to transmit signals spatially through molecule from an allosteric site – a that is distinct orthosteric binding sites primary, endogenous ligands functional or active site. This review starts with historical overview and description classical example allostery hemoglobin other well-known examples (aspartate transcarbamoylase, Lac repressor, kinases, G-protein-coupled receptors, adenosine triphosphate synthase, chaperonin). We then discuss fringe allostery, including intrinsically disordered proteins inter-enzyme influence dynamics, entropy, conformational ensembles landscapes on mechanisms, capture essence field. Thereafter, we give over central methods for investigating molecular covering experimental techniques as well simulations artificial intelligence (AI)-based methods. conclude allostery-based drug discovery, its challenges opportunities: recent advent AI-based methods, compounds are set revolutionize discovery medical treatments.

Language: Английский

Citations

0
Biased signaling in drug discovery and precision medicine DOI
Ren-Lei Ji, Ya‐Xiong Tao

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108804 - 108804

Published: Feb. 1, 2025

Language: Английский

Citations

0
Communication pathway analysis within protein-nucleic acid complexes DOI Open Access
Sneha Bheemireddy,

Roy González-Alemán,

Emmanuelle Bignon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Inter-residue communication forms a vast and intricate network that underpins essential biological processes such as catalysis, gene expression, cell signaling. Allostery, crucial phenomenon where distant regions of macromolecule are energetically coupled to elicit functional responses, operates through these networks within macromolecular complexes. Despite the pivotal role nucleic acids in networks, their contributions allostery remain largely overlooked. To address this gap, we developed ComPASS, large-scale computational method designed study protein-protein protein-nucleic acid Recognizing significance dynamics macromolecules, our approach leverages molecular (MD) simulation data extract inter-residue key properties, including dynamical correlations, interactions, distances. These properties integrated construct weighted comprehensively represents dependencies among amino nucleotides. Using uncovered distinct mechanisms signal transmission diverse systems. In Cysteinyl-tRNA synthetase, central domain was found mediate coordination between substrate recognition enzymatic activity, ensuring precision. LacI repressor, allosteric occurs interface pathways dimer, effectively linking ligand sensing DNA binding. For Type IIF restriction endonuclease Bse634I, structural across dimer tetramer interfaces for specific recognition. liver X receptor, helical region identified bridge connecting ligand-binding events interactions. Finally, analysis with ComPASS aligned previous literature, confirmed H2A L1 loops mediating histone coordinating interactions domains nucleosome is available an open-source tool, maintained at https://github.com/yasamankarami/compass . By offering framework studying advances understanding conformational dynamics, particularly

Language: Английский

Citations

0
The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives DOI

E. Srinivasan,

Grigor Arakelov, Nikolay V. Dokholyan

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169060 - 169060

Published: March 1, 2025

Language: Английский

Citations

0
Can Deep Learning Blind Docking Methods be Used to Predict Allosteric Compounds? DOI Creative Commons
Eric A. Chen, Yingkai Zhang

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Allosteric compounds offer an alternative mode of inhibition to orthosteric with opportunities for selectivity and noncompetition. Structure-based drug design (SBDD) allosteric introduces complications compared their counterparts; multiple binding sites interest are considered, often is only observed in particular protein conformations. Blind docking methods show potential virtual screening ligands, deep learning methods, such as DiffDock, achieve state-of-the-art performance on protein-ligand complex prediction benchmarks traditional Vina Lin_F9. To this aim, we explore the utility a data-driven platform called minimum distance matrix representation (MDMR) retrospectively predict recently discovered inhibitors complexed Cyclin-Dependent Kinase (CDK) 2. In contrast other representations, it uses residue-residue (or residue-ligand) feature that prioritizes formation interactions. Analysis highlights variety conformations ligand modes, identify intermediate conformation heuristic-based kinase classification do not distinguish. Next, self- cross-docking assess whether can both modes if prospective success conditional selection receptor conformation, respectively. We find combined method, DiffDock followed by Lin_F9 Local Re-Docking (DiffDock + LRD), must be selected pose. summary, work value method outlines challenges SBDD compounds.

Language: Английский

Citations

0