Direct Spectroscopic Evidence for an n→π* Interaction

Singh, Santosh Kumar; Mishra, Kamal K.; Sharma, Neha; Das, Aloke

doi:10.1002/ange.201511925

Cited by 18 publications

(14 citation statements)

References 34 publications

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“…C═O···C═O n→π* interaction is characterized by a short O···C═O distance (d) of less than 3.22 Å [the sum of van der Waals radii of carbon and oxygen atom 28 ], bond angle ∠O···C═O ( θ ) of ~109° and the pyramidality (Δ, Θ) of the acceptor carbon atom towards the donor oxygen atom 9 , 14 , 17 , 25 , 29 . Direct spectroscopic evidence for n→π* interaction was recently reported by using gas-phase infrared spectroscopy 30 .…”

Section: Introductionmentioning

confidence: 98%

Reciprocal carbonyl–carbonyl interactions in small molecules and proteins

et al. 2017

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Carbonyl-carbonyl n→π* interactions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the π* orbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a “reciprocal” carbonyl-carbonyl interaction with substantial back and forth n→π* and π→π* electron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding.

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Section: Introductionmentioning

confidence: 98%

Reciprocal carbonyl–carbonyl interactions in small molecules and proteins

et al. 2017

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“…the C atom) have been found and investigated in many families of compounds. [1][2][3][4][5][6][7][8][9][10][11][12] The nature of such interactions has been the subject of discussion for a long time. 13,14 It seems clear nowadays that lone paircarbonyl interactions imply the combination of orbital and electrostatic contributions.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Substituents on the Nature and Strength of Lone-Pair–Carbonyl Interactions in Acyl Halides

Velásquez

Echeverría

Álvarez

2019

Crystal Growth & Design

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We have performed a combined structural and theoretical analysis of lone paircarbonyl interactions in several families of acyl halides (R-CO-X). CSD searches have allowed us to establish the geometrical preferences for such short contacts.The study of the molecular electrostatic potential (MEP) of several molecules along with energy decomposition analyses (EDA) disclosed the nature of the interaction and the factors that affect its strength. To further understand lone pair-carbonyl contacts we have systematically analysed, by means of DFT calculations, the effect of the lone pair as well as of the halogen atom (X) and the substituent attached to the carbonyl group (R). Interaction energies up to 8 kcal/mol suggest that these interactions can be exploited in crystal design and supramolecular chemistry.

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“…The alkoxy anion is hydrated by a water molecule, which makes a 1.8 Å hydrogen bond with the charged oxygen. This water's lone electron pairs interact with the P1 benzothiazole conjugated π-system through n-π* contacts with distances of 2.8-3.5 Å (Singh et al, 2016;Newberry & Raines, 2017). The benzothiazole nitrogen accepts a 1.7 Å hydrogen bond from another hydration water molecule that is also hydrogen bonded to the Gly143 main-chain N-D with a distance of 1.9 Å.…”

Section: Adaptation Of M Pro Active Site Electrostatics Upon Bbh-1 Bi...mentioning

confidence: 99%

Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease: room-temperature X-ray and neutron crystallography, binding thermodynamics, and antiviral activity

Kneller

Phillips

et al. 2022

Preprint

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The COVID-19 pandemic continues to disrupt everyday life, with constantly emerging SARS-CoV-2 variants threatening to render current vaccines ineffective. Small-molecule antivirals can provide an important therapeutic treatment option that is subject to challenges caused by the virus variants. The viral main protease (Mpro) is critical for the virus replication and thus is considered an attractive drug target for specific protease inhibitors. We performed the design and characterization of three reversible covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2, whose structures were derived from those of hepatitis C protease inhibitors boceprevir and narlaprevir. A joint X-ray/neutron structure of the Mpro/BBH-1 complex demonstrated that a Cys145 thiolate reaction with the inhibitor’s keto-warhead creates a negatively charged oxyanion, similar to that proposed for the Mpro-catalyzed peptide bond hydrolysis. Protonation states of the ionizable residues in the Mpro active site adapt to the inhibitor, which appears to be an intrinsic property of Mpro. Structural comparisons of the hybrid inhibitors with PF-07321332 revealed unconventional interactions of PF-07321332 with Mpro which may explain its more favorable enthalpy of binding and consequently higher potency. BBH-1, BBH-2 and NBH-2 demonstrated comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

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Direct Spectroscopic Evidence for an n→π* Interaction

Cited by 18 publications

References 34 publications

Reciprocal carbonyl–carbonyl interactions in small molecules and proteins

Reciprocal carbonyl–carbonyl interactions in small molecules and proteins

Effect of the Substituents on the Nature and Strength of Lone-Pair–Carbonyl Interactions in Acyl Halides

Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease: room-temperature X-ray and neutron crystallography, binding thermodynamics, and antiviral activity

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