Binding Energy Partition of Promising IRAK‐4 Inhibitor (Zimlovisertib) for the Treatment of COVID‐19 Pneumonia

Abstract

The technique of Fragment‐Based Drug Design (FBDD) considers the interactions of different moieties of molecules with biological targets for the rational construction of potential drugs. One basic assumption of FBDD is that the different functional groups of a ligand interact with a biological target in an approximately additive, that is, independent manner. We investigated the interactions of different fragments of ligands and Interleukin‐1 Receptor‐Associated Kinase 4 (IRAK‐4) throughout the FBDD design of Zimlovisertib, a promising anti‐inflammatory, currently in trials to be used for the treatment of COVID‐19 pneumonia. We utilised state‐of‐the‐art methods of wave function analyses mainly the Interacting Quantum Atoms (IQA) energy partition for this purpose. By means of IQA, we assessed the suitability of every change to the ligand in the five stages of FBDD which led to Zimlovisertib on a quantitative basis. We determined the energetics of the interaction of different functional groups in the ligands with the IRAK‐4 protein target and thereby demonstrated the adequacy (or lack thereof) of the changes made across the design of this drug. This analysis permits to verify whether a given alteration of a prospective drug leads to the intended tuning of non‐covalent interactions with its protein objective. Overall, we expect that the methods exploited in this paper will prove valuable in the understanding and control of chemical modifications across FBDD processes.

The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study

“…It is important to note that the topological energy decomposition IQA used in this work does not use any shortcuts to include thousands of atoms but instead focuses on the ~120-atom system size in a full and proper QM analysis. A recent report increased the ligand–protein studied system size with IQA to the ~200 atoms mark [ 57 ].…”