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

[Image: see text] 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 M(u) (3 kcal/mol in the water environment) is the most thermodynamically stable, in fact, it is the cytosine-like tautomer M(c) that plays the main role. There are several reasons, as follows: (1) A large part of M(u) exists as a more stable but inactive form M(u)-m that is unable to pair with adenine. (2) The phosphorylated form of M(c) is only 1 kcal/mol less stable than M(u) in the water environment and thus is readily available for building into the RNA strand, where the M(u)/M(c) energy gap increases and the probability of M(c) → M(u) interconversion leading to C → U mutation is high. (3) The guanine-M(c) complex has similar stability to guanine-cytosine, but the adenine-M(u) complex has lower stability than adenine-uracil. Additionally, the guanine-M(c) complex has a suboptimal distorted geometry that further facilitates the mutations. (4) The activation barrier for proton transfer leading to M(u)-m interconversion into a cytosine-like tautomer is higher than for M(u), 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.