Thermodynamic and Kinetic Characteristics of Molnupiravir Tautomers and Its Complexes with RNA Purine Bases as an Explanation of the Possible Mechanism of Action of This Novel Antiviral Medicine: A Quantum-Chemical Study.

Abstract

The mechanism of action of molnupiravir, a novel antiviral drug, was analyzed from the point of view of its tautomerism by means of quantum-mechanical calculations. It was established that although the uracil-like tautomer Mu (3 kcal/mol in the water environment) is the most thermodynamically stable, in fact, it is the cytosine-like tautomer Mc that plays the main role. There are several reasons, as follows: (1) A large part of Mu exists as a more stable but inactive form Mu-m that is unable to pair with adenine. (2) The phosphorylated form of Mc is only 1 kcal/mol less stable than Mu in the water environment and thus is readily available for building into the RNA strand, where the Mu/Mc energy gap increases and the probability of Mc → Mu interconversion leading to C → U mutation is high. (3) The guanine-Mc complex has similar stability to guanine-cytosine, but the adenine-Mu complex has lower stability than adenine-uracil. Additionally, the guanine-Mc complex has a suboptimal distorted geometry that further facilitates the mutations. (4) The activation barrier for proton transfer leading to Mu-m interconversion into a cytosine-like tautomer is higher than for Mu, which makes the uracil-like form even less available. These facts confirm an intriguing experimental observation that molnupiravir competes mainly with cytosine and not uracil.