Comparative analysis further delineates vector requirements for productive engagement of KRAS-facing regions, providing a structure-based framework for future optimization of aminobenzo[d]isothiazole 1,1-dioxide SOS1 ligands.
Abstract
SOS1 is a guanine nucleotide exchange factor that promotes KRAS activation by catalyzing GDP release and GTP loading, making SOS1-mediated nucleotide exchange an attractive therapeutic target in KRAS-driven cancers. Herein, we report the synthesis, biophysical characterization, and structural analysis of aminobenzo[d]isothiazole 1,1-dioxide SOS1 ligands. Compound 6f engaged SOS1 with a KD of 570 nM by microscale thermophoresis, supported by surface plasmon resonance. X-ray crystal structures of SOS1 bound to compounds 6b and 6f refined previous binding hypotheses regarding pocket engagement. Rather than being dominated by sulfone-mediated contacts, SOS1 recognition is primarily driven by hydrophobic and aromatic packing within the canonical pocket, a conserved ligand NH hydrogen bond to Asn879, and π-π stacking with Tyr884, recapitulating key features of BI-3406 binding. Comparative analysis further delineates vector requirements for productive engagement of KRAS-facing regions, providing a structure-based framework for future optimization of aminobenzo[d]isothiazole 1,1-dioxide SOS1 ligands.
1,4-Dioxane is a widespread groundwater contaminant frequently co-occurring with chlorinated solvents. The group-6 propane monooxygenase (PRM) from Mycobacterium dioxanotrophicus PH-06 degrades dioxane efficiently, yet the molecular determinants underlying its broad substrate spectrum and inhibition behavior remain unresolved. Here, we combined AlphaFold2-based structure prediction, molecular docking, and alchemical free energy calculations to systematically characterize ligand binding in PH-06 PRM. The catalytic center (residues 87–265), coordinated by two histidines and four glutamates, exhibited calculated binding free energies for five substrates (C2–C4 alkanes and cyclic ethers) that significantly correlated with experimentally determined degradation rates (p < 0.05), supporting the ability of ligand binding thermodynamics to capture major substrate-recognition trends in PH-06 PRM. In addition, we identified a remote binding site (residues 329–446) approximately 30 Å from the catalytic center. Thermodynamic analysis indicates that this remote site can attract methane and ethane, potentially limiting their access to the catalytic center. Comparative binding analyses of three common chlorinated solvent inhibitors (i.e., trichloroethylene [TCE], 1,1-dichloroethylene [DCE], and 1,1,1-trichloroethane [TCA]) revealed distinct site preferences consistent with their experimentally observed inhibition modes. Noncompetitive inhibitors (DCE and TCA) displayed stronger affinity for the remote site, whereas the competitive inhibitor TCE exhibited comparable affinity for both binding regions. Sequence conservation, contact probability analysis, and Gene Ontology enrichment further suggest the structural relevance of the remote site and its possible role in ligand recognition and inhibitor selectivity. These findings demonstrate that the AlphaFold-guided free energy calculations can capture experimentally observed substrate and inhibitor trends in PH-06 PRM, while identifying a remote ligand-binding pocket that warrants further mechanistic investigation.
Yishai Gilron, Jose Manuel Diaz Antunes, Devi Kumari Dhakal Gaudel et al.· Journal of Chemical Informat...· 0 citations
G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key biological processes and represent attractive targets for therapeutic intervention. In this study, we report the design, synthesis, and biophysical evaluation of a new family of water-soluble heptacyclic oligo-heteroaryl ligands tailored for G4 recognition. The synthetic route, based on a modular and convergent approach, enables late-stage functionalization and overcomes common limitations of macrocyclic scaffolds such as low yields and poor tractability. The new compounds incorporate 1,2,4-oxadiazole and 1,2,3-triazole units as bioisosteric replacements for oxazole and systematically vary the nature of the central atoms (C vs N) and pendant groups to investigate their effect on G4 binding. All derivatives displayed high aqueous solubility under physiological conditions and selective stabilization of G4 structures, particularly the parallel LTR-IV motif. Biophysical studies and docking calculations indicate that these ligands operate primarily through groove-binding interactions. Notably, no substantial differences were observed between nitrogen- and carbon-substituted analogues, suggesting a conserved binding profile across the series. These findings identify a versatile class of G4 binders with favorable solubility and structural tunability, laying the groundwork for the development of functionalized derivatives for chemical biology and therapeutic applications.
Giorgia Fracchioni, A. M. Caramiello, M. Nadai et al.· ACS Omega· 0 citations
AIMS
To synthesize and evaluate a series of thiosemicarbazone derivatives (2a-2g) incorporating thiophene-2-carboxylic acid as urease inhibitors.
MATERIALS AND METHODS
The compounds were synthesized and characterized using modern spectroscopic techniques. In vitro urease inhibition was determined followed by computational analysis including docking, density functional theory (DFT), molecular dynamics simulations (MD), normal mode analysis (NMA), and SwissADME profiling. Compounds 2g, 2d, and 2b emerged as potent inhibitors with IC50 values of 5.48 ± 0.18 to 9.44 ± 0.32 µM, outperforming the reference thiourea (IC50 = 22.13 ± 2.82 µM). Structure-Activity Relationship (SAR) analysis revealed that electron-withdrawing nitro substituents at para positions dramatically enhanced inhibitory potency. Docking investigation demonstrated robust interactions with the urease active site that includes binuclear nickel center and residues His492, His519, and Asp633. DFT calculations established strong correlations between chemical reactivity indices and biological activity. Molecular docking and MD simulations validated stable binding interactions with key residues (His492, His519, and Asp633). NMA revealed enhanced flap flexibility (λ1 = 1.39 × 10-6) and motional coupling upon 2g binding.
CONCLUSION
These results expose the synthesized compounds, especially 2g as a potent urease inhibitor and provide a valuable insight for future anti-urease drug development.
W. Khan, Laiba, Imtiaz Ahmad et al.· Future Medicinal Chemistry· 0 citations
Covalent probes and therapeutics must balance electrophilicity and stability for function in biological systems, yet gains in stability can sacrifice proteome coverage and limit ligand discovery. Here, we show that single-atom N-to-C substitutions of sulfonyl purines at the nucleofuge position decouple reactivity from stability. Systematic chemical proteomic profiling identifies sulfonyl-imidazopyridines as a class of electrophiles with enhanced cellular and in vivo stability while retaining tunable reactivity toward functional tyrosine and lysine sites. These electrophiles expand access to proteomic sites not engaged by parent sulfonyl-purines or related -triazoles. Importantly, the differential binding of N7- vs N9-sulfonyl-imidazopyridine regioisomer pairs expedites the discovery of proteome-wide-selective inhibitors of metabolic targets, including lanosterol synthase (LSS), phosphoglycerate mutase 1 (PGAM1), and DCTP pyrophosphatase 1 (DCTPP1). Collectively, this work establishes a general strategy for stabilizing electrophiles and introduces a platform for global ligandability mapping guided by regioselective recognition.
Zhihong Li, Madeleine L. Ware, Phillip W. Gingrich et al.· Journal of the American Chem...· 0 citations
Selective targeting of integrin αVβ6 is of high relevance for molecular imaging and therapeutic applications, yet ligands combining high affinity with structural and functional versatility remain limited. A structure-activity relationship (SAR) study of the nonapeptide cyclo-(-Asp-Leu-Ala-Phe-d-Pro-NMeLys-Phe-Arg-Gly-) was performed through site-specific substitution of phenylalanine residues by tryptophan and halogenated tryptophan derivatives, revealing a pronounced position-dependent effect on integrin recognition. Substitution at position i+3 relative to the RGD sequence with halotryptophans is identified as an affinity hotspot, enabling picomolar binding to αVβ6. In contrast, modification at position i+6 preserves high αVβ6 affinity while providing exceptional tolerance toward structural diversification and enabling late-stage functionalization of unprotected peptides via palladium-catalyzed cross-coupling reactions. This establishes i+6 modification as a versatile platform for chemoselective derivatization without compromising affinity. Halotryptophans serve both as pharmacophores and synthetic handles. Notably, an anthracenyl-functionalized derivative combines sub-nanomolar αVβ6 affinity with water solubility and intrinsic fluorescence, demonstrating that even bulky π-systems can be accommodated at discrete positions without loss of potency. These integrin ligands are compatible with cellular applications and enable receptor-specific detection by flow cytometry (FACS) as well as visualization by confocal fluorescence microscopy. This work defines a robust design for αVβ6-targeting functional probes for molecular imaging and fluorescence-guided tumor detection.
Beate Nachtigall, Caroline Brinkmann, J. Langosch et al.· Chemistry· 0 citations
Nine mechanochemically prepared 4′-(N,N-dimethylamino)azobenzene-n-carboxamides (n = 2–4) derived from α-amino acid esters were structurally characterized. X-ray diffraction on single crystals of chiral amides reveals a notably high incidence of structures with Z′ > 1 (five out of eight). Structural analysis indicates that this behavior arises from a combination of synthon frustration, conformational flexibility, and competing intermolecular interactions. Hirshfeld surface and interaction energy analyses show that crystal packing is predominantly governed by dispersion forces. Comparative packing analysis including identification of the isostructural pairs across the ortho-, meta-, and para-series demonstrate that both the azobenzene moiety and the amino acid side chain modulate packing motifs. Pseudosymmetry analysis confirms that the observed high-Z′ packing is a consequence of molecular chirality, conformational variability, and diverse interaction patterns. Complementary Cambridge Structural Database analysis supports an above-average propensity for high-Z′ structures in α-amino acid ester amides, with derivatives of Glu methyl ester, Trp, and Phe showing a particularly increased likelihood of high-Z′ packing.
Alen Bjelopetrović, Sara Morasi Piperčić, Marina Juribašić Kulcsár· Crystal Growth & Design· 0 citations
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