Modeling π–π Interactions with the Effective Fragment Potential Method: The Benzene Dimer and Substituents

Smith, Toni; Slipchenko, Lyudmila V.; Gordon, Mark S.

doi:10.1021/jp800107z

Cited by 77 publications

(80 citation statements)

References 62 publications

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“…16 Various substituents on aromatic rings can greatly influence interaction energies. 1720 As the primary phenyl ring of ebselen and both ebselen derivatives contain selenium and a carbonyl substituent, the more favorable interactions are not surprising and can be attributed to dispersive and other interactions that are not further characterized here. Thus, both ebselen derivatives are capable of forming favorable stacking interactions with Phe254, which is expected to contribute to initial drug recognition and binding.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

“…This interaction increases the distance between the guanidinium moiety and the amide nitrogen by 1.3 A when compared to ebselen and azido ebselen. 20 This increase in distance may be the cause for the reduced interaction energies calculated for the Arg239-adamantyl ebselen model. The calculated interaction energies for Arg239-ebselen suggest more favorable interactions than guanidinium-benzene.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives

et al. 2017

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Previous studies identified ebselen as a potent in vitro and in vivo inhibitor of the Mycobacterium tuberculosis (Mtb) antigen 85 (Ag85) complex, comprising three homologous enzymes required for the biosynthesis of the mycobacterial cell wall. In this study, the Mtb Ag85C enzyme was cocrystallized with azido and adamantyl ebselen derivatives, resulting in two crystallographic structures of 2.01 and 1.30 Å resolution, respectively. Both structures displayed the anticipated covalent modification of the solvent accessible, noncatalytic Cys209 residue forming a selenenylsulfide bond. Continuous difference density for both thiol modifiers allowed for the assessment of interactions that influence ebselen binding and inhibitor orientation that were unobserved in previous Ag85C ebselen structures. The kinact/KI values for ebselen, adamantyl ebselen, and azido ebselen support the importance of observed constructive chemical interactions with Arg239 for increased in vitro efficacy toward Ag85C. To better understand the in vitro kinetic properties of these ebselen derivatives, the energetics of specific protein−inhibitor interactions and relative reaction free energies were calculated for ebselen and both derivatives using density functional theory. These studies further support the different in vitro properties of ebselen and two select ebselen derivatives from our previously published ebselen library with respect to kinetics and protein−inhibitor interactions. In both structures, the α9 helix was displaced farther from the enzyme active site than the previous Ag85C ebselen structure, resulting in the restructuring of a connecting loop and imparting a conformational change to residues believed to play a role in substrate binding specific to Ag85C. These notable structural changes directly affect protein stability, reducing the overall melting temperature by up to 14.5 °C, resulting in the unfolding of protein at physiological temperatures. Additionally, this structural rearrangement due to covalent allosteric modification creates a sizable solvent network that encompasses the active site and extends to the modified Cys209 residue. In all, this study outlines factors that influence enzyme inhibition by ebselen and its derivatives while further highlighting the effects of the covalent modification of Cys209 by said inhibitors on the structure and stability of Ag85C. Furthermore, the results suggest a strategy for developing new classes of Ag85 inhibitors with increased specificity and potency.

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Section: ■ Results and Discussionmentioning

confidence: 97%

Section: ■ Results and Discussionmentioning

confidence: 99%

Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives

et al. 2017

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“…This broader distance range is likely caused by divers chemical moieties attached to aromatic rings in ligand molecules. It has been reported that adding a substituent to one of the rings in the benzene dimer impacts the π-π interaction energy and geometry compared to unsubstituted systems [65] . Specifically, Monte Carlo simulations demonstrated that the presence of a substituent tends to increase the inter-monomer separation in perpendicular conformations.…”

Section: Discussionmentioning

confidence: 99%

Aromatic interactions at the ligand–protein interface: Implications for the development of docking scoring functions

Bryliński

2017

Chem Biol Drug Des

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The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand-protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand-protein complexes, considering various combinations of aromatic amino acid residues and ligand rings. The geometry of interfacial π-π stacking in crystal structures accords with experimental and theoretical data collected for simple systems, such as the benzene dimer. Many contemporary ligand docking programs implicitly treat aromatic stacking with van der Waals and Coulombic potentials. Although this approach generally provides a sufficient specificity to model aromatic interactions, the geometry of π-π contacts in high-scoring docking conformations could still be improved. The comprehensive analysis of aromatic geometries at ligand-protein interfaces lies the foundation for the development of type-specific statistical potentials to more accurately describe aromatic interactions in molecular docking. A Perl script to detect and calculate the geometric parameters of aromatic interactions in ligand-protein complexes is available at https://github.com/michal-brylinski/earomatic. The dataset comprising experimental complex structures and computer-generated models is available at https://osf.io/rztha/.

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“…[36–39] A C 54 fragment was cut out from the center of the SWNTs and the external carbons were terminated with H atoms. The H positions were then optimized at the DFT-D3/BLYP/6-31G level while keeping the C atoms fixed.…”

Section: Methodsmentioning

confidence: 99%

Change in chirality of semiconducting single-walled carbon nanotubes can overcome anionic surfactant stabilisation: a systematic study of aggregation kinetics

et al. 2015

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Single-walled carbon nanotubes’ (SWNT) effectiveness in applications is enhanced by debundling or stabilization. Anionic surfactants are known to effectively stabilize SWNTs. However, the role of specific chirality on surfactant-stabilized SWNT aggregation has not been studied to date. The aggregation behavior of chirally enriched (6,5) and (7,6) semiconducting SWNTs, functionalized with three anionic surfactants—sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS), and sodium deoxycholate (SDOCO)—was evaluated with time-resolved dynamic light scattering. A wide range of mono- (NaCl) and di-valent (CaCl2) electrolytes as well as a 2.5 mg TOC/L Suwannee River humic acid (SRHA) were used as background chemistry. Overall, SDBS showed the most effectiveness in SWNT stability, followed by SDOCO and SDS. However, the relatively larger diameter (7,6) chiral tubes compromised the surfactant stability, compared to (6,5) chiral enrichment, due to enhanced van der Waals interaction. The presence of di-valent electrolytes overshadowed the chirality effects and resulted in similar aggregation behavior for both the SWNT samples. Molecular modeling results enumerated key differences in surfactant conformation on SWNT surfaces and identified interaction energy changes between the two chiralities to delineate aggregation mechanisms. The stability of SWNTs increased in the presence of SRHA under 10 mM monovalent and mixed electrolyte conditions. The results suggest that change in chirality can overcome surfactant stabilization of semiconducting SWNTs. SWNT stability can also be strongly influenced by the anionic surfactant structure.

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Modeling π–π Interactions with the Effective Fragment Potential Method: The Benzene Dimer and Substituents

Cited by 77 publications

References 62 publications

Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives

Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives

Aromatic interactions at the ligand–protein interface: Implications for the development of docking scoring functions

Change in chirality of semiconducting single-walled carbon nanotubes can overcome anionic surfactant stabilisation: a systematic study of aggregation kinetics

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