Cl–π Interactions in Protein–Ligand Complexes

Imai, Yumi; Inoue, Yoshihisa; Nakanishi, Isao; Kitaura, Kazuo

doi:10.1002/qsar.200860168

Cited by 28 publications

(20 citation statements)

References 20 publications

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“…For example, a 3,4-dichloro substitution of the benzene A ring increased the activity within two series of compounds by more than 100-fold (Tahirovic et al, 2008;Mosely et al, 2009). The apparent formation of a -interaction between GluN2B Phe114 and the ligand A ring can in part explain the increased activity induced by the addition of chlorine atoms in the meta and para positions of the A ring (Imai et al, 2008;Matter et al, 2009). From the crystal structure of GluN1/GluN2B ATD in complex with ifenprodil and our docking studies, we speculate that a -interaction takes place between the -hole of the para-positioned chloro and GluN2B Phe114 (e.g., Fig.…”

Section: Figmentioning

confidence: 83%

Mapping the Binding of GluN2B-SelectiveN-Methyl-d-aspartate Receptor Negative Allosteric Modulators

Burger¹,

Yuan²,

Karakaş³

et al. 2012

Mol Pharmacol

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We have used recent structural advances in our understanding of the N-methyl-D-aspartate (NMDA) receptor amino terminal domain to explore the binding mode of multiple diaryl GluN2B-selective negative allosteric modulators at the interface between the GluN1 and GluN2B amino-terminal domains. We found that interaction of the A ring within the binding pocket seems largely invariant for a variety of structurally distinct ligands. In addition, a range of structurally diverse linkers between the two aryl rings can be accommodated by the binding site, providing a potential opportunity to tune interactions with the ligand binding pocket via changes in hydrogen bond donors, acceptors, as well as stereochemistry. The most diversity in atomic interactions between protein and ligand occur in the B ring, with functional groups that contain electron donors and acceptors providing additional atomic contacts within the pocket. A cluster of residues distant to the binding site also control ligand potency, the degree of inhibition, and show ligand-induced increases in motion during molecular dynamics simulations. Mutations at some of these residues seem to distinguish between structurally distinct ligands and raise the possibility that GluN2B-selective ligands can be divided into multiple classes. These results should help facilitate the development of well tolerated GluN2B subunit-selective antagonists.

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Section: Figmentioning

confidence: 83%

Mapping the Binding of GluN2B-SelectiveN-Methyl-d-aspartate Receptor Negative Allosteric Modulators

Burger¹,

Yuan²,

Karakaş³

et al. 2012

Mol Pharmacol

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“…Another interesting observation from the seven structures is how the presence of a "-Cl" or "-NH" functional group influences the orientation of F206 and F297 and, consequently, the overall volume of the active site. Recent analysis of Cl-p and NH-p interactions in protein ligand complexes found in the PDB revealed the presence of two different geometries when these groups interact with aromatic rings: edge-on, where the -Cl or -NH group approaches the aromatic atoms or bonds on the periphery of the ring, or face-on, where the group interacts with the electron density at the center of the aromatic ring (Scrutton and Raine, 1996;Imai et al, 2008;Dalkas et al, 2014). The aromatic ring of the phenylalanine side chain preferred edge-on geometry for -Cl atoms, which were found predominantly in crystallographic structures at a distance range of 3.7-4.1 Å (Imai et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison

et al. 2015

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X-ray crystal structures of complexes of cytochromes CYP2B6 and CYP2A6 with the monoterpene sabinene revealed two distinct binding modes in the active sites. In CYP2B6, sabinene positioned itself with the putative oxidation site located closer to the heme iron. In contrast, sabinene was found in an alternate conformation in the more compact CYP2A6, where the larger hydrophobic side chains resulted in a significantly reduced activesite cavity. Furthermore, results from isothermal titration calorimetry indicated a much more substantial contribution of favorable enthalpy to sabinene binding to CYP2B6 as opposed to CYP2A6, consistent with the previous observations with (1)-a-pinene. Structural analysis of CYP2B6 complexes with sabinene and the structurally similar (3)-carene and comparison with previously solved structures revealed how the movement of the F206 side chain influences the volume of the binding pocket. In addition, retrospective analysis of prior structures revealed that ligands containing -Cl and -NH functional groups adopted a distinct orientation in the CYP2B active site compared with other ligands. This binding mode may reflect the formation of Cl-p or NH-p bonds with aromatic rings in the active site, which serve as important contributors to protein-ligand binding affinity and specificity. Overall, the findings from multiple techniques illustrate how drugs metabolizing CYP2B6 and CYP2A6 handle a common hydrocarbon found in the environment. The study also provides insight into the role of specific functional groups of the ligand that may influence the binding to CYP2B6.

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“…Several studies in the literature have described the effect of ligands with -Cl and/or -NH functional groups on the formation of stable -p bonds with aromatic side chains via an edge-on or face-on geometry at a distance of 3.7-4.1 Å (Scrutton and Raine, 1996;Imai et al, 2008). A -Cl functional group bound to an aromatic ring, such as the chlorophenyl moiety, has a greater propensity for a stable -Cl-p interaction than a -Cl bound to nonaromatic ligand moieties (Matter et al, 2009).…”

Section: Structural Computational and Functional Analysis Of Cyp2b3mentioning

confidence: 99%

Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism

et al. 2016

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Crystal structures of CYP2B35 and CYP2B37 from the desert woodrat were solved in complex with 4-(4-chlorophenyl)imidazole (4-CPI). The closed conformation of CYP2B35 contained two molecules of 4-CPI within the active site, whereas the CYP2B37 structure demonstrated an open conformation with three 4-CPI molecules, one within the active site and the other two in the substrate access channel. To probe structurefunction relationships of CYP2B35, CYP2B37, and the related CYP2B36, we tested the O-dealkylation of three series of related substrates-namely, 7-alkoxycoumarins, 7-alkoxy-4-(trifluoromethyl)coumarins, and 7-alkoxy-4-methylcoumarinswith a C1-C7 side chain. CYP2B35 showed the highest catalytic efficiency (k cat /K M ) with 7-heptoxycoumarin as a substrate, followed by 7-hexoxycoumarin. In contrast, CYP2B37 showed the highest catalytic efficiency with 7-ethoxy-4-(trifluoromethyl) coumarin (7-EFC), followed by 7-methoxy-4-(trifluoromethyl) coumarin (7-MFC). CYP2B35 had no dealkylation activity with 7-MFC or 7-EFC. Furthermore, the new CYP2B-4-CPI-bound structures were used as templates for docking the 7-substituted coumarin derivatives, which revealed orientations consistent with the functional studies. In addition, the observation of multiple -Cl and -NH-p interactions of 4-CPI with the aromatic side chains in the CYP2B35 and CYP2B37 structures provides insight into the influence of such functional groups on CYP2B ligand binding affinity and specificity. To conclude, structural, computational, and functional analysis revealed striking differences between the active sites of CYP2B35 and CYP2B37 that will aid in the elucidation of new structure-activity relationships.

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Cl–π Interactions in Protein–Ligand Complexes

Cited by 28 publications

References 20 publications

Mapping the Binding of GluN2B-SelectiveN-Methyl-d-aspartate Receptor Negative Allosteric Modulators

Mapping the Binding of GluN2B-SelectiveN-Methyl-d-aspartate Receptor Negative Allosteric Modulators

Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison

Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism

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