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

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 targe...

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Published in:Chemphyschem 2022-12, Vol.23 (24), p.e202200455-n/a
Main Authors: Zapata‐Acevedo, César A., Guevara‐Vela, José Manuel, Popelier, Paul L. A., Rocha‐Rinza, Tomás
Format: Article
Language:English
Subjects:
Adequacy
biological chemistry and chemical biology
COVID-19
Drug Design
Functional groups
Humans
interacting quantum atoms
Interleukins
IRAK-4
Kinases
Ligands
Pneumonia
Proteins
Wave functions
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Summary: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 electronic energy was divided throughout the Fragment‐Based Drug Design (FBDD) process of the drug Zimlovisertib using the Interacting Quantum Atoms method. The authors could thereby establish the suitability of the chemical modifications in each step of FBDD, providing a valuable test through an FBDD process.
ISSN:1439-4235
1439-7641
DOI:10.1002/cphc.202200455