Artificial intelligence streamlines scientific discovery of drug–target interactions

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Drug discovery is a complicated process through which new therapeutics are identified to prevent and treat specific diseases. Identification of drug–target interactions (DTIs) stands as pivotal aspect within the realm drug development. The traditional discovery, especially identification DTIs, marked by its high costs experimental assays low success rates. Computational methods have emerged indispensable tools, those employing artificial intelligence (AI) methods, could streamline process, thereby reducing time consumption potentially increasing In this review, we focus on application AI techniques in DTI prediction. Specifically, commence with comprehensive overview development, along systematic prediction validation DTIs. We proceed highlight prominent databases toolkits used developing for prediction, well methodologies evaluating their efficacy. further extend exploration into three primary types state‐of‐the‐art including classical machine learning, deep learning network‐based methods. Finally, summarize key findings outline current challenges future directions that face scientific

Language: Английский

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Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation

Aging, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (WRN) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without cure. While, as we previously reported, depleted NAD+ causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial changes WS and impact on pathologies were unknown. We show that loss WRN increases senescence mesenchymal stem cells (MSCs) likely related dysregulation pathways. In line this, augmentation, via supplementation nicotinamide riboside, reduces improves profiles MSCs knockout (WRN-/-) primary fibroblasts derived compared controls. Moreover, deficiency results decreased (measured indirectly mitochondrially-expressed PARP activity), altered expression key salvage pathway enzymes, including NMNAT1 NAMPT; ChIP-seq data analysis unveils potential co-regulatory axis between NMNATs, important for chromatin stability DNA metabolism. However, restoration or cellular not sufficient reinstall proliferation immortalized siRNA-mediated knockdown WRN, highlighting an indispensable role even affluent environment. Further cell animal studies are needed deepen our understanding underlying mechanisms, facilitating drug development.

Language: Английский

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G‐Protein‐Coupled Receptor 84 Aggravates Early Brain Injury via Microglial NLRP3‐ASC Inflammasome After Subarachnoid Hemorrhage

Brain and Behavior, Journal Year: 2025, Volume and Issue: 15(4)

Published: April 1, 2025

ABSTRACT Background Subarachnoid hemorrhage (SAH) is one of the most devastating hemorrhagic strokes. SAH causes neuroinflammation and leads to both early brain injury delayed injury. G‐protein‐coupled receptor 84 (GPR84), orphan class‐A G protein‐coupled receptors (GPCRs), exerts pro‐inflammatory pro‐phagocytic effects via targeting microglia in central nervous system (CNS). This research investigated role GPR84 on pathology neuroinflammation. Methods An enzyme‐linked immunosorbent assay was used for expression cerebrospinal fluid (CSF) samples from patients with SAH. experimental SAH‐model mouse established by stereotactic injection autologous blood into chiasmatic cisterna. The model vitro exposing hemoglobin. After inhibition mice GPR84‐siRNA GPR84‐antagonist 3, neurological deficits were evaluated modified Garcia test, beam balance Morris water maze. Neuronal death Nissl staining. GPR84, NLRP3 inflammasome, cAMP/PKA expressions detected western blot immunofluorescence. Results upregulated after onset. increased onset, activated promoted IL‐1β secretion. Both GPR84‐shRNA 3 improved mice. Mechanistically, inflammasome signaling pathway aggravate neuronal Conclusions promotes NLRP3‐mediated pyroptosis inflammation pathway.

Language: Английский

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A deep learning framework combining molecular image and protein structural representations identifies candidate drugs for pain

Cell Reports Methods, Journal Year: 2024, Volume and Issue: unknown, P. 100865 - 100865

Published: Sept. 1, 2024

Language: Английский

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Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: June 17, 2024

Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics particularly urgent considering long list late-stage drug candidate failures. Although our knowledge on pathogenic mechanisms driving neurodegeneration growing, additional efforts are required to achieve better ultimately complete understanding pathophysiological underpinnings NDDs. Beyond etiology NDDs being heterogeneous multifactorial, this process further complicated by fact that current experimental models only partially recapitulate major phenotypes observed in humans. In such scenario, multi-omic approaches have potential accelerate identification new or repurposed drugs against multitude underlying One advantage for implementation these overarching tools able disentangle disease states model perturbations through comprehensive characterization distinct molecular layers (i.e., genome, transcriptome, proteome) up single-cell resolution. Because recent advances increasing their affordability scalability, use omics technologies drive nascent, but rapidly expanding neuroscience field. Combined with increasingly advanced vitro models, which benefited from introduction human iPSCs, multi-omics shaping paradigm NDDs, prediction screening. review, we discuss examples, main advantages open challenges targets therapies

Language: Английский

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Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(10), P. 11646 - 11664

Published: Oct. 19, 2024

Neurodegenerative disorders, particularly Alzheimer's and Parkinson's diseases, continue to challenge modern medicine despite therapeutic advances. Orphan G-protein-coupled receptors (GPCRs) have emerged as promising targets in the central nervous system, offering new avenues for drug development. This review focuses on structural biology of orphan GPCRs implicated these providing a comprehensive analysis their molecular architecture functional mechanisms. We examine recent breakthroughs determination techniques, such cryo-electron microscopy X-ray crystallography, which elucidated intricate conformations receptors. The highlights how insights inform our understanding GPCR activation, ligand binding signaling pathways. By integrating data with pharmacology, we explore potential structure-guided approaches developing targeted therapeutics toward GPCRs. structural-biology-centered perspective aims deepen comprehension guide future discovery efforts neurodegenerative disorders.

Language: Английский

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Integrative Analysis of Multi Omic Data

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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