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.
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
[Category] update2024,
[Article Type] article
[Source] pmc
All Keywords