Tautomeric Equilibria of Cytosine and Isocytosine in Gas Phase and in Solution

Abstract

Tautomerism is very important in computer-aided drug design because numerous compounds in small molecule databases could exist in different tautomeric structures. Structure determines the functionality of a small molecule when it is docked to the binding site of a target protein. Thus, if the structure of the ligand is not the most stable tautomer in the protein environment, the properties of the resulting protein-ligand complex will not be accurately calculated. Tautomeric equilibrium of a compound is highly influenced by the medium. For a specific ligand and its derivatives, it is therefore essential to understand potential links of tautomer stability in different media, as this information helps determine the tautomeric forms of a ligand used in docking studies.Cytosine and isocytosine are of pharmaceutical importance. It has been reported that cytosine and its derivatives can bind to the active site of E. Coli IspE protein, which is one of the attractive targets for the development of novel drugs against malaria and tuberculosis. Isocytosine and its derivatives are inhibitors of β-secretase (BACE-1) which is a key target for the treatment of Alzheimer's disease. Both cytosine and isocytosine can exist in a number of tautomers. Understanding the relative stability of these tautomers in the gas phase and aqueous solution will help design inhibitors of IspE protein and BACE-1. We determined the two most stable tautomers of cytosine and isocytosine in gas phase by calculating the relative free energies of these tautomers. The tautomers with the lowest free energies in gas phase were then modeled in aqueous solution, free energy of solvation of these molecules have been calculated. The solvent effect on tautomeric equilibrium of cytosine and isocytosine will be discussed in detail.