The beyond-Rule-of-5 (bRo5) chemical space is a source of new oral drugs and includes large and flexible compounds. Because of their size and conformational variability, bRo5 molecules assume different privileged conformations in the compartments of human body, i. e., they can exhibit chameleonic properties. The elucidation of the ensemble of 3D structures explored by such molecules under different conditions is therefore critical to check the role played by chameleonicity to modulate cell permeability. Here we characterized the conformational ensembles of rifampicin, a bRo5 drug, in polar and nonpolar solvents and in the solid state. We performed NMR experiments, analyzed their results with a novel algorithm and set-up a pool of ad hoc in silico strategies to investigate crystallographic structures retrieved from the CSD. Moreover, a polarity descriptor often related to permeability (SA-3D-PSA) was calculated for all the conformers and its variation with the environment analyzed. Results showed that the conformational behavior of rifampicin in solution and in the solid state is not superposable. The identification of dynamic intramolecular hydrogen bonds can be assessed by NMR spectroscopy but not by X-ray structures. Moreover, SA-3D-PSA revealed that dynamic IMHBs do not provide rifampicin with chameleonic properties. Overall, this study highlights that the peculiarity of rifampicin, which is cell permeable probably because of the presence of static IMHBs but is devoid of any chameleonic behavior, can be assessed by a proper analysis of experimental 3D structures.

Managing Experimental 3D Structures in the Beyond-Rule-of-5 Chemical Space : The Case of Rifampicin / G. Ermondi, F. Lavore, M. Vallaro, G. Tiana, F. Vasile, G. Caron. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 27:40(2021 Jul 16), pp. 10394-10404. [10.1002/chem.202100961]

Managing Experimental 3D Structures in the Beyond-Rule-of-5 Chemical Space : The Case of Rifampicin

G. Tiana;F. Vasile
;
2021

Abstract

The beyond-Rule-of-5 (bRo5) chemical space is a source of new oral drugs and includes large and flexible compounds. Because of their size and conformational variability, bRo5 molecules assume different privileged conformations in the compartments of human body, i. e., they can exhibit chameleonic properties. The elucidation of the ensemble of 3D structures explored by such molecules under different conditions is therefore critical to check the role played by chameleonicity to modulate cell permeability. Here we characterized the conformational ensembles of rifampicin, a bRo5 drug, in polar and nonpolar solvents and in the solid state. We performed NMR experiments, analyzed their results with a novel algorithm and set-up a pool of ad hoc in silico strategies to investigate crystallographic structures retrieved from the CSD. Moreover, a polarity descriptor often related to permeability (SA-3D-PSA) was calculated for all the conformers and its variation with the environment analyzed. Results showed that the conformational behavior of rifampicin in solution and in the solid state is not superposable. The identification of dynamic intramolecular hydrogen bonds can be assessed by NMR spectroscopy but not by X-ray structures. Moreover, SA-3D-PSA revealed that dynamic IMHBs do not provide rifampicin with chameleonic properties. Overall, this study highlights that the peculiarity of rifampicin, which is cell permeable probably because of the presence of static IMHBs but is devoid of any chameleonic behavior, can be assessed by a proper analysis of experimental 3D structures.
bRo5; chameleonicity; intramolecular hydrogen bonds; macrocycles; NMR spectroscopy
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore CHEM-05/A - Chimica organica
16-lug-2021
10-giu-2021
Article (author)
File in questo prodotto:
File Dimensione Formato  
Chemistry A European J - 2021 - Ermondi - Managing Experimental 3D Structures in the Beyond‐Rule‐of‐5 Chemical Space The.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.6 MB
Formato Adobe PDF
1.6 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/851645
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 12
  • ???jsp.display-item.citation.isi??? 11
social impact