2026· Methods in molecular biology· Vol 3061, pp.
187-221
· 0 citations
Medicine
TL;DR
This chapter provides an overview, with literature examples, of underexplored interactions that contribute to molecular binding, including weak hydrogen bonding; anion-π and cation-π interactions; Bürgi-Dunitz and tetrel interactions; halogen and chalcogen bonding; and S···π, C···π, O···π, N···π, and amide···π interactions.
Sulfur-containing heterocycles such as thiophene, thiazole, and thiadiazole frequently appear in biologically active molecules, although the intrinsic nature of their S···O chalcogen-bonding (ChB) interactions in protein–ligand complexes is yet to be completely understood. In this work, a comprehensive survey of the Protein Data Bank (December 2024 release) was carried out, identifying more than 3,000 crystal structures in which these heterocycles engage in chalcogen-bonding interaction. Among those, 1547 unique structures show S···O close contacts with the oxygen atom of the protein carbonyl group and/or side chain. Statistical analysis of distance and angular distributions reveals distinct interaction preferences across the three heterocyclic families. Representative complexes were examined using truncated structures, enabling comparison between crystallographic geometries and optimized gas-phase structures. Quantum chemical calculations, including AIM, NBO, ESP, and EDA analyses, show that electron-withdrawing substituents enhance the stability of S···O ChB interaction by increasing the positive potential on sulfur and lowering the energy of theσC−S*orbital (LUMO). Thiadiazoles exhibit the strongest intrinsic ChB ability, followed by thiazoles and thiophenes. Together, these results provide a detailed molecular-level understanding of S···O ChB interaction and insights into the structural and energetic factors governing the interaction of sulfur-containing ligands within protein environments.
Unknown authors· Journal of Physical Chemistr...· 0 citations
Molecular docking is a cornerstone technique in structure-based drug design (SBDD), providing a computationally efficient approach for predicting ligand–receptor interactions. However, conventional docking programs fail to accurately identify chalcogen bonds (ChBs), which play crucial roles in molecular recognition. Here, we present ChalcoVina, an augmented molecular docking program based on AutoDock Vina that simultaneously evaluates intermolecular and intramolecular ChBs for the first time. An intermolecular ChB term was incorporated into the Vina scoring function using 14,049 sets of quantum-mechanically derived geometric and energetic data. An empirical function constructed from prior knowledge and statistical data was further introduced to account for intramolecular ChBs. Docking experiments demonstrated that ChalcoVina improved docking success rates by 3.3%–13.1% and the geometric reproduction rate of intramolecular ChBs by approximately 23%, which significantly refined the prediction of binding poses. These enhancements expand the applicability of molecular docking for drug discovery involving sulfur-containing compounds. Furthermore, the approach for constructing and integrating ChB terms can be a blueprint for other σ-hole-mediated interactions, facilitating the inclusion of more nonclassical interactions in SBDD.
Unknown authors· Journal of Chemical Informat...· 0 citations
Theoceptor method can be applied to X-ray crystallography- or cryo-electron microscopy-derived structures, can be applied equally to covalent and noncovalent binders, and can provide excellent predictions for the changes in activity between matched molecular pairs.
Nikeel Cull, Yixin He, Sylvia C. Kaempf et al.· Methods in molecular biology· 0 citations
Halogen bonding (XB) is often analyzed in terms of isolated dimers, yet under realistic solution conditions, it coexists with a dense, rapidly fluctuating network of weaker contacts whose net effect on bond strength is difficult to quantify. Here, we combine gas-phase quantum-chemical calculations with explicit-solvent ab initio molecular dynamics (AIMD) in chloroform to dissect how specific noncovalent interactions modulate the I···N halogen bond in ortho-, meta-, and para-C6F4I2···HMTA complexes. Gas-phase DFT, Quantum Theory of Atoms in Molecules (QTAIM), Natural Bond Orbital (NBO), and SAPT0 analyses show that the intrinsic I···N bond in the three isomers is relatively strong and nearly degenerate, with equilibrium distances around 2.83 Å and very similar electronic descriptors. In contrast, AIMD in CHCl3 reveals that the solution-phase geometry reflects a dynamic balance between frequent, short-lived C-H···N contacts to HMTA, which act anticooperatively and lengthen the halogen bond by ≈0.02-0.05 Å, and less populated but more cooperative donor-side C-H···I and C-H···F contacts to the C6F4I2 fragment, which shorten it by up to ≈0.05 Å. A contact-resolved and microstate-based analysis shows that each isomer samples a small number of recurrent solvation motifs with characteristic patterns of C-H···N/C-H···I/C-H···F coordination, and that the relative populations of these motifs control the average I···N distance in solution. Targeted cluster calculations containing only one additional interaction at a time demonstrate that extra C-I···N halogen bonds are intrinsically anticooperative toward the primary I···N bond, whereas C-H···F hydrogen bonding, π···π stacking, and especially C-H···I contacts provide genuine cooperative reinforcement, in line with the trends observed in AIMD. Together, these results establish a quantitative solution-phase hierarchy of cooperative and anticooperative motifs around σ-hole donors and rationalize why gas-phase dimers systematically overestimate halogen-bond robustness relative to chloroform solution, where anticooperative C-H···N hydrogen bonding is ubiquitous. More broadly, the combination of explicit-solvent AIMD with contact-resolved and microstate-based analysis provides a transferable framework for dissecting environmental cooperativity in halogen-bonded and other σ-hole-driven assemblies in liquid phases.
D. V. Krutin, A. Titova, M. Kaplanskiy et al.· Journal of Physical Chemistr...· 0 citations
In this study, a pyridinone-based compound was structurally characterized and computationally analyzed using integrated experimental and theoretical methods. The single-crystal X-ray diffraction (SC-XRD) results confirmed that the molecule adopts a non-planar conformation stabilized by strong N–H···O hydrogen bonds and weak π–π interactions. Density Functional Theory (DFT) calculations reveal a wide HOMO–LUMO energy gap (7.12 eV), indicative of high molecular stability and polar nature. Molecular docking simulations were carried out against Topoisomerase II (PDB ID: 3QX3) to investigate the binding affinity and interaction profile. The compound exhibited a moderate binding energy of –5.23 kcal/mol, dominated by van der Waals, hydrogen bonding, and π–π stacking interactions, suggesting a stable binding orientation within the enzyme’s active site. The combined results highlight the structural stability, electronic properties, and biointeraction potential of the synthesized ligand, supporting its relevance for future structure–activity relationship and anticancer studies.
G. Karakaya, Erdal Kurt, G. Yakalı et al.· Süleyman Demirel Üniversites...· 0 citations
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