title: Carboxymethylsulfonylated Ribopyrimidines: Rational Design of Ribonuclease A Inhibitors Employing Chemical Logic.
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 -SO2CH2CO2H, 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 -SO2CH2CO2H group. The "down" configuration of the 2'-OH group enhanced the inhibitory properties (Ki =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.
authors.affiliation: Department of Chemistry, Indian Institute of Technology (IIT)-Kharagpur, Kharagpur, 721302, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Datta
authors.affiliation: Department of Chemistry, Indian Institute of Technology (IIT)-Kharagpur, Kharagpur, 721302, India. swagata@chem.iitkgp.ernet.in.
authors.forename: Swagata
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Chemistry, Indian Institute of Technology (IIT)-Kharagpur, Kharagpur, 721302, India. tpathak@chem.iitkgp.ernet.in.
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Pathak
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry; D004587:Electrophoresis, Agar Gel; D007700:Kinetics; D062105:Molecular Docking Simulation; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000085:Acetates; D011741:Pyrimidine Nucleosides; D012263:Ribonucleosides; D013450:Sulfones; D012259:Ribonuclease, Pancreatic
keywords: carboxymethylsulfonyls; inhibitors; molecular modeling; ribonuclease A; ribose recognition