Acidic‐Amino‐Acid‐Conjugated Dinucleosides as Ribonuclease A Inhibitors: Rational Design and Effect of Backbone Chirality on Enzyme Inhibition. Issue 6 (24th February 2017)

• Record Type: Journal Article
• Authors: Datta, Dhrubajyoti; Mondal, Pampa; Dasgupta, Swagata; Pathak, Tanmaya
• Is Part Of: ChemistrySelect. Volume 2:Issue 6(2017)
• Page Start: 2106
• Page End: 2113
• Publication Date: 2017-02-24
• Subjects: chiral backbone -- docking -- inhibitors -- modified dinucleoside -- ribonuclease A; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201700253
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: Molecular docking studies identified a dinucleoside connected withd ‐aspartic acid residue as a more suitable competitive inhibitor of ribonuclease A. The chirality carbon of thed ‐aspartic acid residue imposes a curvature in the molecule which is expected to make it a better inhibitor than itsl ‐aspartic acid congener due to more efficient binding with the active site. Experimental data established that the rational design of a dinucleoside by incorporating the predefined chirality in the backbone of the dinucleoside resulted in a half‐fold decrease of the inhibition constant compared to that of thel ‐aspartic acid modified analogue. The dinucleoside also showed better lipophilicity as well as lower toxicity and opens up a new strategy for designing new class of inhibitors for RNase A. Abstract : Molecular docking based information evoked the importance of the substrate chirality for 'receptor‐ligand' recognition. In this context, d ‐aspartic acid conjugated dinuclosides proved to be more efficient than that of thel ‐analogue for RNase A inhibition. The phenomenon was explained by the inhibitor's close approach towards the P1 active site of the enzyme. The low Ki values from Lineweaver‐Burk plots substantiated the fact.