Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein-ligand-bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.
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http://dx.doi.org/10.1039/d1sc04638a | DOI Listing |
Sci Rep
January 2025
Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, No. 950 Donghai Street, Fengze District, Quanzhou, 362000, Fujian, China.
The significance of ALKBH5 in erasing mRNA methylation in mRNA biogenesis, decay, and translation control has emerged as a prominent research focus. Additionally, ALKBH5 is associated with the development of numerous human cancers. However, it remains unclear whether ALKBH5 regulates the growth and metastasis of papillary thyroid carcinoma (PTC).
View Article and Find Full Text PDFGene
January 2025
Department of Epidemiology, School of Public Health, Center of Clinical Epidemiology and Evidence Based Medicine, Shanxi Medical University, Taiyuan, China; MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, Shanxi, China. Electronic address:
Objective: To investigate the relationship between DNA methylation of cord blood apoptosis genes and low birth weight (LBW).
Methods: A case-control study was conducted on 50 pairs of LBW neonates and normal birth weight. Genome-wide methylation assay was performed using Illumina Human Methylation EPIC microarray to analyze the methylation sites of apoptosis-related genes BCL-2, CASP3, and CASP8.
Nanomedicine
January 2025
College of Life Science and Technology, Changchun University of Science and Technology, Changchun 130022, Jilin, China. Electronic address:
Exploiting the unique physiological and biochemical characteristics of the tumor microenvironment, the development of a polypeptide nanogel capable of responding to these specific properties holds great promise as an effective antitumor strategy. In this study, we synthesized a glutathione-responsive (GSH-responsive) methylated poly (ethylene glycol)-poly (phenylalanine)-poly (cystine) block copolymer (mPPC) through one-step ring-opening polymerization. Shikonin (SHK) was encapsulated within nanogel, designated as mPPC/SHK.
View Article and Find Full Text PDFAppl Biochem Biotechnol
January 2025
Centre for Applied Research, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India.
Nelumbo nucifera, an aquatic crop cultivated throughout Asian countries, belongs to the Nelumbonaceae family and has been widely used in traditional medicines with key pharmacological activities such as anti-viral, antipyretic, antioxidant, anti-steroid, anti-inflammatory, anti-arrhythmia, anti-obesity, and anti-aging properties. The present study aims to explore and assess the phytochemical composition, GC-MS profiling, antioxidant efficacy, and the major phytoconstituent phytol subjected to theoretical spectroscopic characterization using the DFT method. The phytochemical profiling of N.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
January 2025
Beijing University of Chemical Technology, State Key Laboratory of Organic-Inorganic Composites, 15 North Third Ring Road East, 37830, Beijing, CHINA.
Polymers with strong electron-withdrawing groups (e.g., cyano-containing polymers) are attractive for a wide range of applications due to their high dielectric constant and outstanding electrochemical stability.
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