Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation

Blundell, Charles; Packer, Martin J.; Almond, Andrew

doi:10.1016/j.bmc.2013.06.056

Cited by 43 publications

(60 citation statements)

References 55 publications

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“…Thus, the major conformation (∼62%) is characterized by dihedral angles ϕ 12 /ψ 12 = 285/225°and ϕ 23 /ψ 23 = 257/103°, and the minor one (∼38%) is defined by torsional angles ϕ 12 /ψ 12 = 285/225°and ϕ 23 /ψ 23 = 279/173°. Taking into account the fact that the values of ϕ 12 and ψ 12 reported by Blundell et al 59 lie within the range of torsional angles determined by Corzana et al 58 and that the librational amplitudes are 16 and 22°for ϕ 12 and ψ 12 , respectively, it is clear that the conformational preferences of streptomycin primarily depend on the relative arrangement of the R2 and G3 subunits.…”

Section: ■ Resultsmentioning

confidence: 91%

“…This trend agrees with the experimental data, as this group has a bimodal distribution with mean angles of 78 and 162°. 59 The guanidinium group bound at position 3′ adopts a single conformation with a torsional angle (χ 2 ) of 98°, which reflects the unimodal behavior (χ 2 = 128°) found in NMR analysis. 59 Such behavior is dictated by the formation of hydrogen-bond interactions between the guanidinium unit and the oxygen atoms of the glucosamine ring and the hydroxyl group attached to position 5″.…”

Section: ■ Resultsmentioning

confidence: 94%

“…59 The guanidinium group bound at position 3′ adopts a single conformation with a torsional angle (χ 2 ) of 98°, which reflects the unimodal behavior (χ 2 = 128°) found in NMR analysis. 59 Such behavior is dictated by the formation of hydrogen-bond interactions between the guanidinium unit and the oxygen atoms of the glucosamine ring and the hydroxyl group attached to position 5″. Nevertheless, whereas the orientation of this group is predicted to have an average angle (χ 3 ) of 175°, the experimental data reflects a mean angle close to 300°.…”

Section: ■ Resultsmentioning

confidence: 94%

“…To the best of our knowledge, two experimental works have examined the conformational preferences of streptomycin in aqueous solution. 58,59 Using a combination of NMR experiments and computational studies, Corzana et al 58 reported that the three rings of streptomycin are primarily found in two conformational arrangements. The first family has a relative population of 50−60% and is characterized by dihedral angles ϕ 12 /ψ 12 = 270/ 190°and ϕ 23 /ψ 23 = 265/60°.…”

Section: ■ Resultsmentioning

confidence: 99%

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Assessing the Suitability of the Multilevel Strategy for the Conformational Analysis of Small Ligands

et al. 2014

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Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Furthermore, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution.

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Section: ■ Resultsmentioning

confidence: 91%

Section: ■ Resultsmentioning

confidence: 94%

Section: ■ Resultsmentioning

confidence: 94%

Section: ■ Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Assessing the Suitability of the Multilevel Strategy for the Conformational Analysis of Small Ligands

et al. 2014

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“…Related information is being used in medicinal chemistry to design molecules that prefer to adopt a bound structure (68). In fact, this strategy has been successfully applied to HIV protease, BANCE1, and streptomycin (69).…”

Section: Trp3 Interacts With Micelles Via Conformational Selectionmentioning

confidence: 99%

Structural and Dynamic Insights of the Interaction between Tritrpticin and Micelles: An NMR Study

Santos

Moraes

Nakaie

et al. 2016

Biophysical Journal

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A large number of antimicrobial peptides (AMPs) acts with high selectivity and specificity through interactions with membrane lipid components. These peptides undergo complex conformational changes in solution; upon binding to an interface, one major conformation is stabilized. Here we describe a study of the interaction between tritrpticin (TRP3), a cathelicidin AMP, and micelles of different chemical composition. The peptide's structure and dynamics were examined using one-dimensional and two-dimensional NMR. Our data showed that the interaction occurred by conformational selection and the peptide acquired similar structures in all systems studied, despite differences in detergent headgroup charge or dipole orientation. Fluorescence and paramagnetic relaxation enhancement experiments showed that the peptide is located in the interface region and is slightly more deeply inserted in 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-1 0 -rac-glycerol (LMPG, anionic) than in 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine (LLPC, zwitterionic) micelles. Moreover, the tilt angle of an assumed helical portion of the peptide is similar in both systems. In previous work we proposed that TRP3 acts by a toroidal pore mechanism. In view of the high hydrophobic core exposure, hydration, and curvature presented by micelles, the conformation of TRP3 in these systems could be related to the peptide's conformation in the toroidal pore.

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Artificial Intelligence in Medicinal Chemistry

Griffen

Dossetter

Leach

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Basic concepts in artificial intelligence (AI) are reviewed with reference to their application in medicinal chemistry. Challenges in the representation of molecules and biological data are discussed. The contrast between AI requiring autonomy and machine learning as a set of statistical techniques is highlighted. Key areas of AI in medicinal chemistry are then reviewed: data extraction, computer aided synthesis planning, compound activity, toxicity and ADME property prediction, automated compound design, and integrating all these tasks into automated drug discovery systems. Finally issues of the adoption of AI methods by medicinal chemists, future developments, and the ethics of AI in medicinal chemistry are addressed.

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Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation

Abstract: Graphical abstract

Cited by 43 publications

References 55 publications

Assessing the Suitability of the Multilevel Strategy for the Conformational Analysis of Small Ligands

Assessing the Suitability of the Multilevel Strategy for the Conformational Analysis of Small Ligands

Structural and Dynamic Insights of the Interaction between Tritrpticin and Micelles: An NMR Study

Artificial Intelligence in Medicinal Chemistry

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