Discovery of 14‐3‐3 PPI Stabilizers by Extension of an Amidine‐Substituted Thiophene Fragment DOI Creative Commons
Qi Wu, Federica Centorrino, X. Guillory

и другие.

ChemBioChem, Год журнала: 2023, Номер 25(1)

Опубликована: Окт. 30, 2023

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand 'druggable' proteome and develop new therapeutic strategies. While there have been significant advancements methodologies for developing PPI inhibitors, relative scarcity of literature describing 'bottom-up' development stabilizers (Molecular Glues). The hub protein 14-3-3 its interactome provide an excellent platform exploring conceptual approaches modulation, including evolution chemical matter Molecular Glues. In this study, we employed fragment extension strategy discover complex Estrogen Receptor alpha-derived peptide (ERα). A focused library analogues derived from amidine-substituted thiophene enhanced affinity 14-3-3/ERα up 6.2-fold. Structure-activity relationship (SAR) analysis underscored importance newly added, aromatic side chain certain degree rigidity. X-ray structural revealed unique intermolecular π-π stacking binding mode most active analogues, resulting simultaneous two molecules pocket. Notably, analogue 11 displayed selective stabilization complex.

Язык: Английский

Current perspectives and trend of computer-aided drug design: a review and bibliometric analysis DOI Creative Commons
Zhenhui Wu, Shupeng Chen, Yihao Wang

и другие.

International Journal of Surgery, Год журнала: 2024, Номер unknown

Опубликована: Март 19, 2024

Computer-aided drug design (CADD) is a technique for computing ligand-receptor interactions and involved in various stages of development. To better grasp the frontiers hotspots CADD, we conducted review analysis through bibliometrics.

Язык: Английский

Процитировано

24
Targeting the undruggables—the power of protein degraders DOI Creative Commons
Chao Zhang, Yongbo Liu, Guangchen Li

и другие.

Science Bulletin, Год журнала: 2024, Номер 69(11), С. 1776 - 1797

Опубликована: Март 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Язык: Английский

Процитировано

22
Multi-tiered chemical proteomic maps of tryptoline acrylamide–protein interactions in cancer cells DOI
Evert Njomen, Rachel E. Hayward,

Kristen E. DeMeester

и другие.

Nature Chemistry, Год журнала: 2024, Номер 16(10), С. 1592 - 1604

Опубликована: Авг. 13, 2024

Язык: Английский

Процитировано

14
Molecular glue degraders: exciting opportunities for novel drug discovery DOI
Thomas Lemaître, Marie Cornu, Florian Schwalen

и другие.

Expert Opinion on Drug Discovery, Год журнала: 2024, Номер 19(4), С. 433 - 449

Опубликована: Янв. 19, 2024

Introduction Molecular Glue Degraders (MGDs) is a concept that refers to class of compounds facilitate the interaction between two proteins or molecules within cell. These act as bridge enhances specific Protein-Protein Interactions (PPIs). Over past decade, this technology has gained attention potential strategy target were traditionally considered undruggable using small molecules.

Язык: Английский

Процитировано

10
The BCL-2 protein family: from discovery to drug development DOI Creative Commons
Carlo M. Croce, David L. Vaux, Andreas Strasser

и другие.

Cell Death and Differentiation, Год журнала: 2025, Номер unknown

Опубликована: Апрель 9, 2025

Abstract The landmark discovery of the BCL-2 gene and then its function marked identification inhibition apoptotic cell death as a crucial novel mechanism driving cancer development launched quest to discover molecular control apoptosis. This work culminated in generation specific inhibitors that are now clinical use, saving improving tens thousands lives annually. Here, some original players this story, describe sequence critical discoveries. t(14;18) chromosomal translocation, frequently observed follicular lymphoma, allowed cloning oncogene ( ) juxtaposed immunoglobulin heavy chain locus IgH ). Of note, acted distinct manner compared already known oncogenic proteins like ABL c-MYC. did not promote proliferation but inhibited death, originally shown growth factor dependent haematopoietic progenitor lines (e.g., FDC-P1) Eμ-Myc/Eμ-Bcl-2 double transgenic mice. Following rapid expansion protein family, Abbott Laboratories solved first structure BCL-XL subsequently BCL-XL/BAK peptide complex, opening way understanding structures other family members and, finally, different pro-survival proteins, thanks efforts Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude Gilead. Although inhibitor Venetoclax is use MCL-1 undergoing trials, several questions remain on whether therapeutic windows can be achieved what agents should used combination with BH3 mimetics achieve optimal impact for therapy. Finally, expression BH3-only needs better understood may identify targets story still concluded!

Язык: Английский

Процитировано

1
From part to whole: AI-driven progress in fragment-based drug discovery DOI Creative Commons
Jinyoung Yoo, Wooyoung Jang, Woong‐Hee Shin

и другие.

Current Opinion in Structural Biology, Год журнала: 2025, Номер 91, С. 102995 - 102995

Опубликована: Фев. 18, 2025

Язык: Английский

Процитировано

1
ACFIS 2.0: an improved web-server for fragment-based drug discovery via a dynamic screening strategy DOI Creative Commons
Xing-Xing Shi, Zhi-Zheng Wang, Fan Wang

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 51(W1), С. W25 - W32

Опубликована: Май 9, 2023

Abstract Drug discovery, which plays a vital role in maintaining human health, is persistent challenge. Fragment-based drug discovery (FBDD) one of the strategies for novel candidate compounds. Computational tools FBDD could help to identify potential leads cost-efficient and time-saving manner. The Auto Core Fragment silico Screening (ACFIS) server well-established effective online tool FBDD. However, accurate prediction protein-fragment binding mode affinity still major challenge due weak affinity. Here, we present an updated version (ACFIS 2.0), that incorporates dynamic fragment growing strategy consider protein flexibility. improvements ACFIS 2.0 include (i) increased accuracy hit compound identification (from 75.4% 88.5% using same test set), (ii) improved rationality mode, (iii) structural diversity expanded libraries (iv) inclusion more comprehensive functionality predicting molecular properties. Three successful cases lead are described, including drugs treat Parkinson's disease, cancer, depressive disorder. These demonstrate utility this web-based server. freely available at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS2/.

Язык: Английский

Процитировано

15
Cryo-electron microscopy-based drug design DOI Creative Commons

Ecenur Cebi,

Joohyun Lee, Vinod Kumar Subramani

и другие.

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Март 4, 2024

Structure-based drug design (SBDD) has gained popularity owing to its ability develop more potent drugs compared conventional drug-discovery methods. The success of SBDD relies heavily on obtaining the three-dimensional structures targets. X-ray crystallography is primary method used for solving and aiding workflow; however, it not suitable all With resolution revolution, enabling routine high-resolution reconstruction structures, cryogenic electron microscopy (cryo-EM) emerged as a promising alternative attracted increasing attention in SBDD. Cryo-EM offers various advantages over can potentially replace To fully utilize cryo-EM discovery, understanding strengths weaknesses this technique noting key advancements field are crucial. This review provides an overview general workflow highlights technical innovations that enable application design. Furthermore, most recent achievements methodology discovery discussed, demonstrating potential advancing development. By capabilities cryo-EM, researchers leverage benefits designing effective drugs. concludes with discussion future perspectives cryo-EM-based SBDD, emphasizing role driving integration into process holds great promise accelerating new improved therapeutic agents combat diseases.

Язык: Английский

Процитировано

5
Fragment-based drug discovery campaigns guided by native mass spectrometry DOI
Louise M. Sternicki, Sally‐Ann Poulsen

RSC Medicinal Chemistry, Год журнала: 2024, Номер 15(7), С. 2270 - 2285

Опубликована: Янв. 1, 2024

Native mass spectrometry (nMS) is well established as a biophysical technique for characterising biomolecules and their interactions with endogenous or investigational small molecule ligands such fragments.

Язык: Английский

Процитировано

5
Identification of druggable hub genes and key pathways associated with cervical cancer by protein-protein interaction analysis: An in silico study DOI Creative Commons
Azizeh Asadzadeh, Nafiseh Ghorbani, Katayoun Dastan

и другие.

International Journal of Reproductive BioMedicine (IJRM), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 21, 2023

Background: The uncontrolled growth of abnormal cells in the cervix leads to cervical cancer (CC), fourth most common gynecologic cancer. So far, many studies have been conducted on CC; however, it is still necessary discover hub gene, key pathways, and exact underlying mechanisms involved developing this disease. Objective: This study aims use gene expression patterns protein-protein interaction (PPI) network analysis identify pathways druggable genes CC. Materials Methods: In silico analysis, 2 microarray datasets; GSE63514 (104 24 normal samples), GSE9750 (42 samples) were extracted from omnibus differentially expressed between them. Gene ontology Kyoto encyclopedia genomes pathway performed via Enrichr database. STRING 12.0 database CytoHubba plugin Cytoscape 3.9.1 software implemented create analyze PPI network. Finally, screened. Results: Based degree method, 10 known as after screening networks by plugin. NCAPG, KIF11, TTK, PBK, MELK, ASPM, TPX2, BUB1, TOP2A, KIF2C are genes, which 5 (KIF11, TOP2A) druggable. Conclusion: research provides a novel vision for designing therapeutic targets patients with However, these findings should be verified through additional experiments. Key words: Protein interactions, Cervical cancer, Hub expression, DEGs.

Язык: Английский

Процитировано

10