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Updated: Aug 17, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification of allosteric inhibitor against AKT1 through structure-based virtual screening
Keerthana Karunakaran1, Rajiniraja Muniyan2
1School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, India.
Abstract:
AKT (serine/threonine protein kinase) is a potential therapeutic target for many types of cancer as it plays a vital role in cancer progression. Many AKT inhibitors are already in practice under single and combinatorial therapy. However, most of these inhibitors are orthosteric / pan-AKT that are non-selective and non-specific to AKT kinase and their isoforms. Hence, researchers are searching for novel allosteric inhibitors that bind in the interface between pH and kinase domain. In this study, we performed structure-based virtual screening from the afroDB (a diverse natural compounds library) to find the potential inhibitor targeting the AKT1. These compounds were filtered through Lipinski, ADMET properties, combined with a molecular docking approach to obtain the 8 best compounds. Then we performed molecular dynamics simulation for apoprotein, AKT1 with 8 complexes, and AKT1 with the positive control (Miransertib). Molecular docking and simulation analysis revealed that Bianthracene III (hit 1), 10-acetonyl Knipholonecyclooxanthrone (hit 2), Abyssinoflavanone VII (hit 5) and 8-c-p-hydroxybenzyldiosmetin (hit 6) had a better binding affinity, stability, and compactness than the reference compound. Notably, hit 1, hit 2 and hit 5 had molecular features required for allosteric inhibition.
Insights
Researchers identified novel allosteric AKT1 inhibitors from natural compounds. These compounds show promising binding affinity and stability, offering potential for more selective cancer therapies.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- AKT (serine/threonine protein kinase) is crucial in cancer progression and a therapeutic target.
- Existing AKT inhibitors often lack selectivity, driving the search for novel allosteric inhibitors.
- Allosteric inhibitors offer improved specificity by targeting unique binding sites.
Purpose of the Study:
- To identify novel allosteric inhibitors targeting AKT1 using structure-based virtual screening.
- To evaluate the binding affinity, stability, and molecular features of potential inhibitors.
Main Methods:
- Structure-based virtual screening of the afroDB natural compounds library.
- Filtering compounds based on Lipinski's rule and ADMET properties.
- Molecular docking and molecular dynamics simulations to assess binding and stability.
Main Results:
- Eight potential AKT1 inhibitors were identified through virtual screening and docking.
- Molecular dynamics simulations indicated that Bianthracene III (hit 1), 10-acetonyl Knipholonecyclooxanthrone (hit 2), Abyssinoflavanone VII (hit 5), and 8-c-p-hydroxybenzyldiosmetin (hit 6) exhibit superior binding affinity and stability compared to the control.
- Hits 1, 2, and 5 possess molecular characteristics suitable for allosteric inhibition.
Conclusions:
- Natural compounds from afroDB are a viable source for discovering selective AKT1 allosteric inhibitors.
- Bianthracene III, 10-acetonyl Knipholonecyclooxanthrone, and Abyssinoflavanone VII demonstrate significant potential as allosteric AKT1 inhibitors.
- These findings pave the way for developing more targeted and effective cancer therapeutics.
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