Background:
Remdesivir (GS-5734) has emerged as a promising drug during the challenging times of
COVID-19 pandemic. Being a prodrug, it undergoes several metabolic reactions before converting to its active
triphosphate metabolite. It is important to establish the atomic level details and explore the energy profile of the
prodrug to drug conversion process.
Methods:
In this work, Density Functional Theory (DFT) calculations were performed to explore the entire metabolic path. Further, the potential energy surface (PES) diagram for the conversion of prodrug remdesivir to its active
metabolite was established. The role of catalytic triad of Hint1 phosphoramidase enzyme in P-N bond hydrolysis was
also studied on a model system using combined molecular docking and quantum mechanics approach.
Results:
The overall energy of reaction is 11.47 kcal/mol exergonic and the reaction proceeds through many steps
requiring high activation energies. In the absence of a catalyst, the P-N bond breaking step requires 41.78 kcal/mol,
which is reduced to 14.26 kcal/mol in a catalytic environment.
Conclusion:
The metabolic pathways of model system of remdesivir (MSR) were completely explored completely
and potential energy surface diagrams at two levels of theory, B3LYP/6-311++G(d, p) and B3LYP/6-31+G(d), were
established and compared. The results highlight the importance of an additional water molecule in the metabolic
reaction. The P-N bond cleavage step of the metabolic process requires the presence of an enzymatic environment.
