Insights into features and lead optimization of novel type 1½ inhibitors of p38α mitogen-activated protein kinase using QSAR, quantum mechanics, bioisostere replacement and ADMET studies

Abstract

p38α mitogen-activated protein kinase (p38αMAPK) has been implicated in many diseases yet no inhibitor has been approved for therapeutic use. Various inhibitors have been developed with different binding modes, but none has been approved for use due to the non-specificity of these inhibitors. A novel type of inhibitor developed by Walter et al., and termed Type 1½, showed promising results in vitro with high selectivity for p38αMAPK, improved target retention time (TRT) and high potency. Type 1½ inhibitors combine features of both Type I inhibitors and Type II inhibitors. In this study, we provide insight into these novel inhibitors using QSAR, Molecular docking, and Quantum mechanics. Finally, in a bid to optimize, we generated 523 new sets of lead compounds using Bioisostere replacement methods and predicted the biological activities using the well-validated QSAR model. The results showed that the nhal descriptor (Count of halogen atoms) was the most important contributor to the QSAR model and the newly designed leads showed improved binding free energy than the original inhibitors with predicted pIC50 up to 3.2.

Keywords

• Type 1½ inhibitors
• p38αMitogen-activated protein kinase
• QSAR
• HOMO-LUMO
• E-pharmacophore
• Molecular docking