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 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.

The Tautomeric State of N4-Hydroxycytidine within Base-Paired RNA

“…The authors suggest that the presence of N 4 -hydroxycytosine in the amino form is questionable and the reported ambivalent base pairing capability should be explained by the exclusive presence of the imino form . Recent theoretical studies performed in a water environment suggest that the energy difference between anti -imino and anti -amino forms of NHC-monophosphate is small enough to allow the existence of both tautomers after its administration in vivo , whereas the energy gap between the two tautomers after building into the RNA greatly increases in favor of the imino form . In an oligomer context, mainly reports on the structure and stability of DNA duplexes containing N 4 -methoxycytidine (NMC) were published.…”