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Drug Discovery in the Age of Artificial Intelligence: Transformative Target-Based Approaches.
Int J Mol Sci
November 2024
Center for Research and Education in Nanobioengineering, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
The complexities inherent in drug development are multi-faceted and often hamper accuracy, speed and efficiency, thereby limiting success. This review explores how recent developments in machine learning (ML) are significantly impacting target-based drug discovery, particularly in small-molecule approaches. The Simplified Molecular Input Line Entry System (SMILES), which translates a chemical compound's three-dimensional structure into a string of symbols, is now widely used in drug design, mining, and repurposing.
View Article and Find Full Text PDFRepurposing Hsp90 inhibitors as antimicrobials targeting two-component systems identifies compounds leading to loss of bacterial membrane integrity.
Microbiol Spectr
August 2024
Host-Microbe Interactomics Group, Dept. Animal Sciences, Wageningen University & Research (WUR), Wageningen, the Netherlands.
Unlabelled: The discovery of antimicrobials with novel mechanisms of action is crucial to tackle the foreseen global health crisis due to antimicrobial resistance. Bacterial two-component signaling systems (TCSs) are attractive targets for the discovery of novel antibacterial agents. TCS-encoding genes are found in all bacterial genomes and typically consist of a sensor histidine kinase (HK) and a response regulator.
View Article and Find Full Text PDFProtein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson's phenotypes.
Nat Commun
April 2024
Department of Chemistry and Biochemistry, F.W. Olin Hall, 2190 E Iliff Ave, University of Denver, Denver, CO, 80210, USA.
Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson's disease; therefore, a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation.
View Article and Find Full Text PDFFragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders.
Redox Biol
June 2024
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United States. Electronic address:
The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells.
View Article and Find Full Text PDFDual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis.
Mol Cancer Ther
October 2023
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
Genome-wide gene expression analysis and animal modeling indicate that melanoma differentiation associated gene-9 (mda-9, Syntenin, Syndecan binding protein, referred to as MDA-9/Syntenin) positively regulates melanoma metastasis. The MDA-9/Syntenin protein contains two tandem PDZ domains serving as a nexus for interactions with multiple proteins that initiate transcription of metastasis-associated genes. Although targeting either PDZ domain abrogates signaling and prometastatic phenotypes, the integrity of both domains is critical for full biological function.
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