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

by Selleckchem | Aug 09 2023

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.

Comments:

The passage you provided describes the use of Fragment-Based Drug Design (FBDD) in the development of Zimlovisertib, an anti-inflammatory drug being investigated for the treatment of COVID-19 pneumonia. FBDD involves studying the interactions between different fragments of molecules and a biological target to design potential drugs.

One of the key assumptions of FBDD is that the interactions between different functional groups of a ligand (a molecule that binds to a target) and the biological target are approximately additive and independent of each other. In this study, the researchers investigated the interactions of various fragments of ligands with Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4), a protein target involved in inflammation. They used state-of-the-art methods, particularly Interacting Quantum Atoms (IQA) energy partitioning, to analyze the wave function of the molecular systems.

The researchers aimed to assess the suitability of different changes made to the ligand throughout the five stages of FBDD, which eventually led to the development of Zimlovisertib. By using IQA, they quantitatively determined the energetics of the interactions between different functional groups in the ligands and the IRAK-4 protein target. This analysis allowed them to evaluate whether specific alterations to the prospective drug resulted in the desired tuning of non-covalent interactions with the target protein.

Overall, the researchers expect that the methods employed in this study will provide valuable insights into and control over the chemical modifications involved in the FBDD process. By understanding the interactions between ligand fragments and the protein target at an atomic level, they aim to optimize the design of drugs like Zimlovisertib, potentially leading to improved effectiveness and therapeutic outcomes.