Can an intermediate rate of nitrogen inversion affect drug efficacy?

• Verfasst von: Steimbach, Raphael R. [VerfasserIn]
• Verfasst von: Tihanyi, Gergely [VerfasserIn]
• Verfasst von: Géraldy, Magalie N. E. [VerfasserIn]
• Verfasst von: Wzorek, Alicja [VerfasserIn]
• Verfasst von: Miller, Aubry K. [VerfasserIn]
• Verfasst von: Klika, Karel D. [VerfasserIn]
• Titel: Can an intermediate rate of nitrogen inversion affect drug efficacy?
• Verf.angabe: Raphael R. Steimbach, Gergely Tihanyi, Magalie N. E. Géraldy, Alicja Wzorek, Aubry K. Miller and Karel D. Klika
• E-Jahr: 2021
• Jahr: 20 September 2021
• Umfang: 14 S.
• Fussnoten: Gesehen am 21.02.2022
• Titel Quelle: Enthalten in: Symmetry
• Ort Quelle: Basel : MDPI, 2009
• Jahr Quelle: 2021
• Band/Heft Quelle: 13(2021), 9, Artikel-ID 1753, Seite 1-14
• ISSN Quelle: 2073-8994
• DOI: doi:10.3390/sym13091753
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: diffusion
• Sach-SW: molecular chirality
• Sach-SW: nitrogen inversion
• Sach-SW: protein binding
• Sach-SW: rate determination
• K10plus-PPN: 1793418527

Abstract

Nitrogen-inversion rates and diffusion coefficients were measured using 1H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availability, hence efficacy, of these compounds if they were utilized as drugs. The postulated intermediate range is based on a capture-volume concept, whereby the nitrogen inversion during the time a ligand takes to pass through a volume surrounding the protein binding site, as calculated by the diffusion rate, determines if it will influence ligand binding to the protein. In the systems examined here, the measured nitrogen-inversion rates and the times required to traverse the capture volume differed by a few orders of magnitude. Potentially more consequential are intermediate nitrogen-inversion rates in epimeric cases—since the energies of the interconverting species are unequal, a heavy bias against the eutomer might occur. The implications of an intermediate nitrogen-inversion rate are significant for in silico drug design, drug efficacy, molecular modeling of drug-protein binding, pharmacokinetics, drug enantiomer evaluation, etc. Due consideration of the process should thus be taken into account for drug development directions and in vitro evaluation.