A new screening tool to determine chameleonic properties of macrocycles

Marjanović, Nera; Čikoš, Ana; Koštrun, Sanja

doi:10.1016/j.molstruc.2019.126929

Cited by 3 publications

(7 citation statements)

References 21 publications

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“…Moreover, their molecular modeling calculations placed the Ca 2+ ion in the opposite side of the structure compared to what it is expected from the NMR data of this work. Nonetheless, the results by Dancer et al and Marjanović et al, despite being incomplete, are in good agreement with our findings on the all- trans conformation of CycA upon binding Ca 2+ . In this work, the 1 H and 13 C chemical shifts and ROE assignments of the CycA:Ca 2+ complex are shown in Tables S5, S6, and S8, respectively.…”

Section: Resultssupporting

confidence: 93%

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Structural Flexibility of Cyclosporine A Is Mediated by Amide Cis–Trans Isomerization and the Chameleonic Roles of Calcium

et al. 2021

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Falling outside of Lipinski’s rule of five, macrocyclic drugs have accessed unique binding sites of their target receptors unreachable by traditional small molecules. Cyclosporin(e) A (CycA), an extensively studied macrocyclic natural product, is an immunosuppressant with undesirable side effects such as electrolytic imbalances. In this work, a comprehensive view on the conformational landscape of CycA, its interactions with Ca2+, and host–guest interactions with cyclophilin A (CypA) is reported through exhaustive analyses that combine ion-mobility spectrometry–mass spectrometry (IMS–MS), nuclear magnetic resonance (NMR) spectroscopy, distance-geometry modeling, and NMR-driven molecular dynamics. Our IMS–MS data show that CycA can adopt extremely compact conformations with significantly smaller collisional cross sections than the closed conformation observed in CDCl3. To adopt these conformations, the macrocyclic ring has to twist and bend via cis–trans isomerization of backbone amides, and thus, we termed this family of structures the “bent” conformation. Furthermore, NMR measurements indicate that the closed conformation exists at 19% in CD3OD/H2O and 55% in CD3CN. However, upon interacting with Ca2+, in addition to the bent and previously reported closed conformations of free CycA, the CycA:Ca2+ complex is open and has all-trans peptide bonds. Previous NMR studies using calcium perchlorate reported only the closed conformation of CycA (which contains one cis peptide bond). Here, calcium chloride, a more biologically relevant salt, was used, and interestingly, it helps converting the cis -MeLeu9–MeLeu10 peptide bond into a trans bond. Last, we were able to capture the native binding of CycA and CypA to give forth evidence that IMS–MS is able to probe the solution-phase structures of the complexes and that the Ca2+:CycA complex may play an essential role in the binding of CycA to CypA.

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Section: Resultssupporting

confidence: 93%

“…A similar result has been reported by Marjanović et al for CycA:Ca 2+ in tetrahydrofuran (THF). However, the 1 H and 13 C chemical shifts of the CycA:Ca 2+ complex were not reported, so it is not known whether there is any downfield shift of amide protons in THF.…”

Section: Resultssupporting

confidence: 89%

Structural Flexibility of Cyclosporine A Is Mediated by Amide Cis–Trans Isomerization and the Chameleonic Roles of Calcium

et al. 2021

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“…2−11 The experimental results, as obtained by crystallography and NMR, reveal that CsA exhibits chameleonic behaviors, i.e., "closed," "open," "very open" conformations, etc., depending on the environment (solvent polarity, presence of metal ions or micelles, and complex formation with proteins). 2,3,12−18 A crystal structure in the closed conformation with four intramolecular hydrogen bonds (IMHBs; i.e., Abu 2 -H−Val 5 -O, Val 5 -H−Abu 2 -O, Ala 7 -H−Mva 11 -O, and Dal 8 -H−Mle 6 -O) has been reported (ID: DEKSAN, 2 source: CSD). A similarly closed conformation has also been reported in CDCl 3 .…”

Section: ■ Introductionmentioning

confidence: 99%

“…3,15,19−21 For example, it is known that minor conformation(s), which have not be characterized experimentally, constitute 6% of the ensemble in chloroform (CHCl 3 ). 3 A cis-amide conformation might exist between Val 5 and Mle 6 in dimethyl sulfoxide (DMSO). 21 A minimum of six sets of signals have been observed in methanol (MeOH).…”

Section: ■ Introductionmentioning

confidence: 99%

Cyclosporin A: Conformational Complexity and Chameleonicity

Ono

Naylor

Okumura

et al. 2021

J. Chem. Inf. Model.

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The chameleonic behavior of cyclosporin A (CsA) was investigated through conformational ensembles employing multicanonical molecular dynamics simulations that could sample the cis and trans isomers of N-methylated amino acids; these assessments were conducted in explicit water, dimethyl sulfoxide, acetonitrile, methanol, chloroform, cyclohexane (CHX), and n-hexane (HEX) using AMBER ff03, AMBER10:EHT, AMBER12:EHT, and AMBER14:EHT force fields. The conformational details were discussed employing the free-energy landscapes (FELs) at T = 300 K; it was observed that the experimentally determined structures of CsA were only a part of the conformational space. Comparing the ROESY measurements in CHX-d12 and HEX-d14, the major conformations in those apolar solvents were essentially the same as that in CDCl3 except for the observation of some sidechain rotamers. The effects of the metal ions on the conformations, including the cis/trans isomerization, were also investigated. Based on the analysis of FELs, it was concluded that the AMBER ff03 force field best described the experimentally derived conformations, indicating that CsA intrinsically formed membrane-permeable conformations and that the metal ions might be the key to the cis/trans isomerization of N-methylated amino acids before binding a partner protein.

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“…Based on the good oral bioavailability of macrolides, especially azithromycin, used as a starting point for FideltaMacro scaffolds, a low permeability of presented compounds is most likely cumulative effect of chemical instability of the cladinose sugar in acidic conditions, increased molecular weight, and large number of hydrogen bond donors in agreement with the oral bioavailability thresholds determined by Khilberg and Villar (Table S6). Different strategies for optimization of oral bioavailability of macrocycles have been published including methylation of amide bonds, introduction of heterocyclic constrains, side chain optimizations, intra-molecular/trans-annular hydrogen bonds, and stereochemistry variations. − All these strategies, as a net result, influenced the 3D structure of macrocycles, enabling shielding of polar and/or metabolically unstable groups and solvent-induced conformational changes. It has been also demonstrated that the 3D structure and consequently physico-chemical properties and membrane permeability of macrolides are highly influenced by the ring decorations. − Importance of the 3D structure as well as induced conformational changes on the oral absorption of macrocycles were quantified by Whitty et al They concluded that, for high MW compounds, there is no single polar surface area (PSA) cutoff value that can simultaneously satisfy the conditions of 0.2*MW ≤ PSA ≤ 140 Å 2 , required for orally bioavailable small molecules.…”

Section: Resultsmentioning

confidence: 99%

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

et al. 2021

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Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.

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A new screening tool to determine chameleonic properties of macrocycles

Cited by 3 publications

References 21 publications

Structural Flexibility of Cyclosporine A Is Mediated by Amide Cis–Trans Isomerization and the Chameleonic Roles of Calcium

Structural Flexibility of Cyclosporine A Is Mediated by Amide Cis–Trans Isomerization and the Chameleonic Roles of Calcium

Cyclosporin A: Conformational Complexity and Chameleonicity

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

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