Carboxymethylsulfonylated Ribopyrimidines: Rational Design of Ribonuclease A Inhibitors Employing Chemical Logic. (4th March 2016)

• Record Type: Journal Article
• Authors: Datta, Dhrubajyoti; Dasgupta, Swagata; Pathak, Tanmaya
• Is Part Of: ChemMedChem. Volume 11:Number 6(2016)
• Page Start: 620
• Page End: 628
• Publication Date: 2016-03-04
• Subjects: carboxymethylsulfonyls -- inhibitors -- molecular modeling -- ribonuclease A -- ribose recognition; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600007
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Hydrolysis of RNA by ribonuclease A crucially depends on the participation of the 2′‐OH group as well as the positioning of the internucleotide bond at two different sites of the enzyme. Therefore, ribopyrimidines were modified with −SO2 CH2 CO2 H, an acidic functional group, which was expected to interact with the phosphate binding site. These ribonucleosides were designed to understand the influence of the 2′‐OH group of these inhibitors on ribonuclease A inhibition along with the effect of the −SO2 CH2 CO2 H group. The "down" configuration of the 2′‐OH group enhanced the inhibitory properties ( K i =1.75 μm ) and also imparted important Val43 H‐bonding with the furanose oxygen atom of the inhibitors. One of the most important aspects of this work is that there was no serendipitous discovery of the inhibitors. The inhibitors reported in this manuscript were obtained by design by employing chemical logic. Abstract : C U later : The "down" configuration of the 2′‐hydroxy group in 3′‐carboxymethylsulfonylated ribouridine and ribocytidine enhances the inhibitory properties, giving rise to low inhibition constants. Docking studies reveal that these inhibitors form an important H‐bond between the Val43 residue and the furanose oxygen atom similar to that of the natural substrate of ribonuclease A.