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.

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