Noncovalent Interactions of π Systems with Sulfur: The Atomic Chameleon of Molecular Recognition

Abstract

The relative strength of noncovalent interactions between at hioether sulfur atom and various p systems in designed top pan molecular balances was determined by NMR spectroscopy. Compared to its oxygen counterpart, the sulfur atom displays aremarkable ability to interact with almost equal facility over the entire range of p systems studied, with the simple alkene emerging as the most powerfulpartner.With the exception of the O···heteroarene interaction, all noncovalent interactions of sulfur with p systems are favoured over oxygen.Noncovalent interactions involving aromatic systems, [1] such as p-p stacking [2] or cation-p interactions, [3] and the ability of an arene to act as ahydrogen-bond acceptor [4] are all firmly established as vital control elements in molecular recognition and consequently underpin vast areas of chemistry and molecular biology.More recently,asaconsequence of two virtually simultaneous theoretical studies predicting the strength of the related anion-p interaction, [5] this area has witnessed intense research activity. [6] In parallel, following on from the seminal observation of the attractive lone pair···p interaction in stabilizing the Z-DNAs tructure, [7] this force is also rapidly gaining recognition as anew area of supramolecular chemistry. [8] Detailed quantifiable knowledge of the relative strength of these weak forces is now therefore considered to be essential for the rational design of organocatalysts, [9] new drugs and supramolecular materials,aswell as the understanding of three-dimensional structure and function in biological systems.Thec onformational analysis of designed molecular balances [10] with limited degrees of freedom is ap articularly powerful tool for probing the strength, distance and angular dependence of such interactions,and also allows for exploration of all important solvation phenomena. [11] Whilst an increasing number of studies in recent years have focused on measuring the O···p interaction with electron-deficient arenes and heteroarenes, [12] we were surprised to note that quantifiable comparative information using such balances to probe noncovalent interactions involving as ulfur atom with p systems has been almost entirely neglected. Thev ital role played by sulfur in chemical and biological recognition and in drug development is well-recognized. [13] As summarized in an ongoing series of excellent reviews, [1] theinvestigation of the S···arene interaction is essentially based on extensive database mining of protein crystal structures.I nasignificant contribution by Dougherty and co-workers, [14] the strength of aS···arene interaction in the dopamine D2 receptor has been probed by progressive modulation of the electrostatic surface of the arene through fluorination. To the best of our knowledge,i ns pite of the fact that theoretical chemists continue to be intrigued by the noncovalent interactions of asulfur atom with p systems, [15] no quantitative experimental measurements have been reported for either simple alkenes or heteroarenes.I nt erms of ac...

Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies

“…CAR, another well-known substrate of P-gp [50], forms hydrophobic interactions with three residues (I306, F314, and F759) in the binding pocket; these interactions are mainly of π character, two of them are π-π type of interaction and one is π-alkyl type of interaction. The docking pose is also forming one π-sulphur type of interaction (Figure 17) between the π electron cloud of one of the aromatic rings in the carbazol structure and the lone pair of electrons cloud of the sulphur atom in M986; π-sulphur interactions have been well-recognized to play an important role in chemical and biological recognition, as well as in drug development [53,54], thus they may have a big contribution in stabilizing the molecule into the receptor binding site. The binding mode of the VER pose ( Figure 18) shows hydrophobic interactions with four residues (Y310, F314, F732, and F728) in the binding pocket, all of them π type of interactions, one π-sigma type of interaction, two π-π type of interaction, and one amide•••π stacking interaction, in which the π-surface of the amide bond between residues I731 and F732 stacks against the π-surface of the one aromatic ring in VER.…”

Discovery of Isaindigotone Derivatives as Novel Bloom’s Syndrome Protein (BLM) Helicase Inhibitors That Disrupt the BLM/DNA Interactions and Regulate the Homologous Recombination Repair

“…43 The top-ranked predict binding mode in MD simulation is shown in Figure 8B. In this binding mode, 29 had π−π stacking interactions with Tyr995 and His996, hydrophobic interactions with Met1111 and Ile1168, 44,45 and hydrogen-bonding interactions with Glu1143, implying that these amino acids might be the crucial residues in 29 binding to BLM (Figure 8B and Table S4 and Figure S12). In addition, slight conformation changes of the DNA binding pocket were observed in the presence of 29 in the MD simulations (Table S5 and Figure S13).…”

Anion-π and lone pair-π interactions with s-tetrazine-based ligands

“…The parallelism of lone pair- with the anion- interactions are evident, as are too their differences. The charge neutrality of the species that provides the non-shared electron pair ensures that the polarization and dispersive components will be larger than the electrostatic component of the global interaction energy, which, in turn, will be generally smaller than that of the corresponding anion- interactions (at least when aromatic systems with a marked -acidity are involved) [153][154][155]. In spite of its intrinsically weak character, the participation of s-tetrazines in lone pair- interactions with non-shared pairs of oxygen and nitrogen atoms in solid phases have been evidenced by x-ray crystallographic studies [73].…”