Conformational analysis of major metabolites of macrolide antibiotics roxithromycin and erythromycin A with different biological properties by NMR spectroscopy and molecular dynamics

Gharbi-Benarous, Josyane; Ladam, Patrick; Delaforge, Marcel; Girault, Jean‐Pierre

doi:10.1039/p29930002303

Cited by 22 publications

(34 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these studies the solution conformation of roxithromycin in chloroform was found to be similar to that in the crystalline state, with the oxime chain being oriented towards the macrocyclic ring, and with some flexibility at the C2–C8 region . Signs for conformational alteration were observed upon comparison of the NMR data obtained in chloroform to that in methanol and solution ensembles were proposed, but with limited certainty . The conformation of telithromycin in aqueous solution has been analysed based on the δ , J , T 1 data and NOEs in combination with restrained MD calculations, providing helpful insights into the flexibility and geometry of the macrocycle, yet without being able to describe the composition of the solution ensemble .…”

Section: Resultsmentioning

confidence: 99%

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

Danelius

Poongavanam

Peintner

et al. 2020

Chemistry A European J

212

View full text Add to dashboard Cite

It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behavea smolecular chameleons to combine otherwisec onflicting properties, including aqueous solubility,c ell permeability and target binding. Evidence for this has, however,b een limited to the cyclic peptidec yclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing al ess pronounced behaviour.I n particular roxithromycin, telithromycin and spiramycin display am arked, yet limited flexibility and populate signifi-cantly less polar and more compact conformational ensembles in an apolart han in ap olar environment. In addition to balancingo fm embrane permeability and aqueous solubility, this flexibility also allows binding to targetst hat vary in structure between species. The drugs' passivec ell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability,d eveloped for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.[a] Dr.

show abstract

Section: Resultsmentioning

confidence: 99%

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

Danelius

Poongavanam

Peintner

et al. 2020

Chemistry A European J

212

View full text Add to dashboard Cite

show abstract

“…This observation is in good agreement with those of previous investigations. 42 , 52 , 53 In aqueous solution, the oxime chain shows higher flexibility and is solvent-exposed in a majority of the conformations, representing 82% of the solution ensemble ( Figure 9 A,B). Only two of the minor conformations in water display intramolecular hydrogen bonds to the oxime side chain, one of them (conformation 2) being found also in chloroform.…”

Section: Resultsmentioning

confidence: 99%

Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?

et al. 2018

View full text Add to dashboard Cite

Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conformations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of a set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE-LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conformational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.

show abstract

“…The structures of the compounds were built from scratch and proton-proton distance restraints were calculated according to the observed NOE's intensities: distance values of 3.0, 4.0 and 5.0 Å were used for strong, intermediate and weak NOE's, respectively. A constant temperature dynamics run with periodic temperature jumps [26] followed, according to the protocol: 8 ps MD at 300 K, temperature jumps at 600 K for 4 ps to provide enough energy to pass conformational barriers, four repetitions of this cycle. A 75 ps MD run at 300 K followed.…”

Section: Molecular Modellingmentioning

confidence: 99%