Tuning the Biological Activity of PI3K<i>δ</i> Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs

Data from: Intramolecular transformation of an antifungal antibiotic nystatin A1 into its isomer, iso-nystatin A1. Structural and molecular modeling studies

Nystatin A₁, a polyene macrolide antifungal antibiotic, in a slightly basic or acidic solution undergoes an intramolecular transformation, yielding a structural isomer, the translactonisation product, <i>iso</i>-nystatin A₁ with lactone ring diminished by two carbon atoms. Structural evidence is provided by advanced NMR and MS studies. Molecular dynamics simulations and quantum mechanics calculations gave the insight into the course and mechanism of the transformation and its effect on the conformation of the subject molecule.<br