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Updated: Dec 18, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Virtual docking screening and QSAR studies to explore AKT and mTOR inhibitors acting on PI3K in cancers
Ilham Kandoussi1, Oussama Benherrif1, Wiame Lakhlili1
1Biotechnology Laboratory (MedBiotech), Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.
Abstract:
The phosphoinositide 3-kinase (PI3K) pathway is an important regulator of cell proliferation and metabolism. PI3K activation initiates a signal transduction cascade, of which the major effectors are the kinases AKT and mTOR. Aberrant activation of the PI3K/AKT/mTOR pathway is frequently observed in many human malignancies and the combination of compounds simultaneously targeting different related molecules in the PI3K/AKT/mTOR pathway leads to synergistic activity. To explore the competing common ATP inhibitors PI3K/AKT and PI3K/mTOR we developed a model PI3K-SAR 2D which made it possible to predict the bioactivity of inhibitors of AKT and mTOR towards PI3K; the interaction of the best inhibitors was evaluated by docking analysis and compared to that of dactolisib and pictilisib. A PI3K-SAR model with a correlation coefficient (R2) of 0.81706 and an RMSE of 0.16029 was obtained, which was validated and evaluated by a cross-validation method, LOO. The most predicted AKT and mTOR inhibitors present respectively pIC50 activities between 9.26-9.93 and 9.59-9.87. After docking and several comparisons, inhibitors with better predictions showed better affinity and interaction with PI3K compared to pictilisib and dactolisib, so we found that 4 inhibitors of AKT and 14 mTOR inhibitors met the criteria of Lipinski and Veber and could be future drugs.
Insights
This study developed a predictive model for phosphoinositide 3-kinase (PI3K) pathway inhibitors. The model identified promising AKT and mTOR inhibitors with potential as future cancer drugs.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- The phosphoinositide 3-kinase (PI3K) pathway regulates cell proliferation and metabolism.
- Aberrant PI3K/AKT/mTOR pathway activation is common in human malignancies.
- Targeting multiple molecules in this pathway can yield synergistic anticancer activity.
Purpose of the Study:
- To develop a predictive model (PI3K-SAR 2D) for evaluating AKT and mTOR inhibitors against PI3K.
- To identify novel drug candidates by assessing inhibitor bioactivity and molecular interactions.
- To compare the efficacy of novel inhibitors with existing drugs like dactolisib and pictilisib.
Main Methods:
- Development and validation of a 2D Quantitative Structure-Activity Relationship (PI3K-SAR 2D) model.
- Utilizing cross-validation (LOO) to ensure model reliability (R2=0.81706, RMSE=0.16029).
- Employing molecular docking analysis to evaluate inhibitor-target interactions.
Main Results:
- The PI3K-SAR 2D model accurately predicted the bioactivity of AKT and mTOR inhibitors.
- Predicted pIC50 activities for top AKT and mTOR inhibitors ranged from 9.26-9.93 and 9.59-9.87, respectively.
- Identified 4 AKT and 14 mTOR inhibitors with favorable drug-like properties (Lipinski and Veber criteria) and superior PI3K interaction compared to pictilisib and dactolisib.
Conclusions:
- The developed PI3K-SAR 2D model is effective for predicting PI3K pathway inhibitor activity.
- Several novel AKT and mTOR inhibitors demonstrate promising therapeutic potential for cancer treatment.
- These identified compounds warrant further investigation as potential drug candidates.
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