The IQA energy partition in a drug design setting: a Hepatitis C virus RNA-dependent RNA polymerase (NS5B) case study

The interaction of the thumb site II of the NS5B protein of Hepatitis C Virus and a pair of drug candidates was studied using a topological energy decomposition method called Interacting Quantum Atoms (IQA). The atomic energies are then processed by the Relative Energy Gradient (REG) method, which extracts chemical insight by computation based on minimal assumptions. REG reveals the most important IQA energy contributions, by atom and energy type (electrostatics, sterics, exchange-correlation), that are responsible for the behaviour of the whole system, systematically from a short range ligand-pocket interaction until a distance of approximately 22 Å. The degree of covalency in various key interatomic interactions can be quantified. No exchange-correlation contribution is responsible for the changes in the energy profile of both pocket-ligand systems investigated in the ligand-pocket distances equal or greater than that of the global minimum. Regarding the hydrogen bonds in the system, a “neighbour effect” was observed thanks to the REG method, which states that a carbon atom would have its covalent neighbour oxygen rather not form a hydrogen bond. The combination of IQA and REG enables the automatic identification of the pharmacophore in the ligands. The coarser Interacting Quantum Fragments (IQF) enables the determination of which amino acids of the pocket contribute most to the binding and the type of energy of said binding. This work is an example of the contribution topological energy decomposition methods can give to fragment-based drug design.

Keywords: interacting quantum atoms; quantum chemical topology; quantum theory of atoms in molecules; fragment based drug design; NS5B; hepatitis C virus; relative energy gradient method