Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers

Abstract

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110γ and p110δ are evolutionarily divergent; they probably need separate strategies for drug development.

• ADME
• Glide
• homology modeling
• Molegro Virtual Docker
• molecular dynamics
• molecular docking
• PI3K AKT pathway inhibitors
• p110 delta structure

Acknowledgements

The work was carried out on Schrodinger software, the team of Schrodinger, India is highly appreciated for assistance in Glide XP docking and result interpretation. The authors would like to thank Mr. Vinod, Dr R. S. Rathore, and Dr S. V. V. Kalyan for their support in data analysis. The M.J.V. would like to thank Prof. KM Ravi Nambiar for his support and encouragement in this project.

Declaration of interest

A.S. would like to thank DBT, India for the financial support.

Supplementary material available online

Supplementary Tables 1 and 2.