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Published on: August 17, 2019
Selectivity Studies and Free Energy Calculations of AKT Inhibitors
Haizhen A Zhong1, David T Goodwin1
1Department of Chemistry, University of Nebraska at Omaha, Omaha, NE 68182, USA.
Abstract:
Protein kinase B (PKB) or AKT protein is an important target for cancer treatment. Significant advances have been made in developing ATP-competitive inhibitors and allosteric binders targeting AKT1. However, adverse effects or toxicities have been found, and the cutaneous toxicity was found to be linked to the inhibition of AKT2. Thus, selective inhibition of AKT inhibitors is of significance. Our work, using the Schrödinger Covalent Dock (CovDock) program and the Movable Type (MT)-based free energy calculation (ΔG), yielded small mean errors for the experimentally derived binding free energy (ΔG). The docking data suggested that AKT1 binding may require residues Asn54, Trp80, Tyr272, Asp274, and Asp292, whereas AKT2 binding would expect residues Phe163 and Glu279, and AKT3 binding would favor residues Glu17, Trp79, Phe306, and Glu295. These findings may help guide AKT1-selective or AKT3-selective molecular design while sparing the inhibition of AKT2 to minimize the cutaneous toxicity.
Insights
Developing selective AKT inhibitors is crucial for cancer therapy to minimize side effects. This study identifies key protein residues for AKT1 and AKT3 selectivity, potentially reducing cutaneous toxicity associated with AKT2 inhibition.
Area of Science:
- Biochemistry
- Computational Chemistry
- Drug Discovery
Background:
- Protein kinase B (PKB), also known as AKT, is a key target in cancer treatment.
- Current AKT inhibitors face challenges including adverse effects, particularly cutaneous toxicity linked to AKT2 inhibition.
- Selective inhibition of AKT isoforms is necessary to improve therapeutic outcomes and reduce toxicity.
Purpose of the Study:
- To computationally identify key residues for selective binding to AKT1, AKT2, and AKT3 isoforms.
- To guide the rational design of AKT1-selective or AKT3-selective inhibitors.
- To minimize cutaneous toxicity by sparing AKT2 inhibition.
Main Methods:
- Utilized Schrödinger Covalent Dock (CovDock) for molecular docking simulations.
- Employed Movable Type (MT)-based free energy calculations (ΔG) to assess binding affinity.
- Analyzed docking data to identify specific amino acid residues involved in isoform binding.
Main Results:
- Docking simulations accurately predicted experimental binding free energies with small mean errors.
- Identified distinct residue requirements for AKT1 (Asn54, Trp80, Tyr272, Asp274, Asp292), AKT2 (Phe163, Glu279), and AKT3 (Glu17, Trp79, Phe306, Glu295) binding.
- The findings provide a basis for differentiating between AKT isoforms.
Conclusions:
- Computational methods, CovDock and MT-based ΔG, are effective for predicting binding free energies.
- Specific residues are crucial for selective binding to AKT1, AKT2, and AKT3.
- This research can inform the development of safer, isoform-selective AKT inhibitors for cancer therapy, mitigating AKT2-related toxicities.
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