From Quantum to Clinic: Theoretical Analysis of GS 441524 Interactions in FIP Treatment via the Schrödinger Equation

Feline infectious peritonitis (FIP) is a devastating coronavirus infection in cats characterized by high mortality [1,5]. Although GS-441524, an adenosine nucleoside analog that inhibits the virus's RNA-dependent RNA polymerase (RdRp) enzyme, has achieved dramatic success in FIP treatment in recent years [6,7], a theoretical analysis of the electronic and quantum mechanical processes underlying the molecule's therapeutic efficacy is of critical importance. In this study, the interaction of the GS-441524 molecule with the target enzyme was investigated using the Density Functional Theory (DFT) method, based on the timeindependent Schrödinger equation ( ̂ψ=Eψ) [13,15]. As a result of the analyses, it was determined that the unshared electron pairs on the nitrogen atoms in the structure of the molecule form a stable complex by establishing stable electrostatic interactions and hydrogen bonds with the amino acid residues in the active site of the enzyme. The low frontier molecular orbital (HOMO-LUMO) energy gap calculated confirms the high electron transfer capability and chemical reactivity of the molecule during its incorporation into the viral RNA chain [21,22]. Furthermore, quantum chemical descriptors derived from the wave function, such as dipole moment and partial atomic charges, were supported by Quantitative StructureActivity Relationship (QSAR) models [24]. Although clinical data compilations indicate an overall success rate of 84.6% for the drug, optimization issues experienced in cases such as neurological involvement [11] demonstrate how decisive quantum mechanical modeling is in future rational drug design and digital optimization of nucleoside analogs [17,26].