Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology

Abstract

Phosphatidylinositol 4-kinase IIIβ (PI4KB) is indispensable for the replication of various positive-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, we report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These "hybrids" not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compounds exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. Our crystallographic analysis unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity.

Negative charge and membrane-tethered viral 3B cooperate to recruit viral RNA dependent RNA polymerase 3D pol

“…3B lower panel), documenting the specificity of the system. As an additional control we performed the phosphorylation reaction in the presence of the specific PI4KB inhibitor MI364 (compound 23 in our recent publication 55 ) and, as expected, we observed only limited recruitment of the mCherry-SidC biosensor to the GUVs (Fig. 3C ).…”

Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs

“…Computational docking is used to predict bound conformations and free binding energies of small molecule ligands to macromolecular targets 26 . Docking is useful for the study of biomolecular interactions and structure-based drug design 27 . Although the calculation of the absolute binding energy from the structures of a ligand-bound state might be inaccurate, the relative ranking of binding energies is generally reliable for the binding of closely related ligands to identical receptors.…”

Quantitative Structure-Activity Relationship Model for HCVNS5B inhibitors based on an Antlion Optimizer-Adaptive Neuro-Fuzzy Inference System

“…In the current study, the highly potent and selective molecular compounds 56 were depend on several descriptors like molecular flexibility (var1), molecular complexity (var2), non-C/H atoms (var3), electronegative atoms (var4), stereo centers (var5), rotatable bonds (var6), rings (var7), aromatic atoms (var8) symmetric atoms (var9), so a curve will be made between these descriptors versus binding energy and PIC50 as in Fig. 14 .…”

“…The MTiOpenScreen is a virtual screening server, which uses Autodock Vina as a docking tool 55 to investigate the highly potent and selective molecular compounds as mentioned before 56 . When using a big data set reaches to 1000 structures, a certain criteria will be applied to ensure a good absorption/penetration of the drugs.…”