Importance of Co‐operative Hydrogen Bonding in the Apramycin‐Ribosomal Decoding A‐Site Interaction. (28th October 2022)

• Record Type: Journal Article
• Authors: Pirrone, Michael G.; Ande, Chennaiah; Haldimann, Klara; Hobbie, Sven N.; Vasella, Andrea; Böttger, Erik C.; Crich, David
• Is Part Of: ChemMedChem. Volume 18:Number 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-28
• Subjects: hydrogen bonding -- aminoglycosides -- antibacterial -- antiribosomal activity -- aminoglycoside modifying enzymes; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200486
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: An intramolecular hydrogen bond between the protonated equatorial 7'‐methylamino group of apramycin and the vicinal axial 6'‐hydroxy group acidifies the 6'‐hydroxy group leading to a strong hydrogen bond to A1408 in the ribosomal drug binding pocket in the decoding A site of the small ribosomal subunit. In 6'‐epiapramycin, the trans‐nature of the 6'‐hydroxy group and the 7'‐methylamino group results in a much weaker intramolecular hydrogen bond, and a consequently weaker cooperative hydrogen bonding network with A1408, resulting overall in reduced inhibition of protein synthesis and antibacterial activity. Abstract : The cis ‐configuration of the equatorial 7'‐methylamino and axial 6'‐alcohols is demonstrated to be a critical element in an essential co‐operative hydrogen bonding network with A1408 in the interaction of the aminoglycoside antibiotic apramycin with the decoding A site of the bacterial ribosome.