Drug repurposing through Biophysical Insights: Focus on Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase
Priyanga Paranthaman1, Ramanathan Karuppasamy1, Shanthi Veerappapillai2
1Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Abstract:
The kynurenine pathway (KP) plays a pivotal role in dampening the immune response in many types of cancer, including TNBC. The intricate involvement of tryptophan degradation via KP serves as a critical regulator in mediating immunosuppression in the tumor microenvironment. The key enzymes that facilitate this mechanism and contribute to tumor progression are indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility. To date, no FDA-approved drugs have advanced for dual targeting of these enzymes. Therefore, this study aimed to repurpose the approved drugs from the DrugBank database as novel IDO1/TDO inhibitors. Initially, 2588 FDA-approved compounds were screened by employing molecular docking and pharmacokinetic profiling. Subsequently, methods such as MM-GBSA calculations and machine learning based analysis precisely identified 20 potential lead compounds. The resultant compounds were then assessed for various toxicity endpoints and anticancer activity. The PaccMann server revealed potent anticancer activity, with sensitivities ranging from 0.203 to 24.119 μM against MDA-MB-231 TNBC cell lines. Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC.
Insights
This study repurposed FDA-approved drugs to find new inhibitors for indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO), key in triple-negative breast cancer (TNBC) immunosuppression. Dapagliflozin (DB06292) emerged as a promising candidate for TNBC management.
Area of Science:
- Biochemistry
- Immunology
- Oncology
Background:
- The kynurenine pathway (KP) and its enzymes, indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO), are crucial in regulating the tumor microenvironment and immune suppression in cancers like triple-negative breast cancer (TNBC).
- Existing dual inhibitors like navoximod have shown limited clinical success due to poor bioavailability and efficacy, highlighting the need for novel therapeutic strategies targeting IDO1 and TDO.
Purpose of the Study:
- To identify novel, FDA-approved drugs that can serve as dual inhibitors of IDO1 and TDO for potential TNBC treatment.
- To repurpose existing drugs to overcome the limitations of current therapeutic approaches targeting the kynurenine pathway.
Main Methods:
- Screening of 2588 FDA-approved compounds using molecular docking and pharmacokinetic profiling.
- Utilizing MM-GBSA calculations and machine learning for lead compound identification, followed by toxicity and anticancer activity assessments.
- Employing the PaccMann server for anticancer activity evaluation and molecular dynamics simulations to confirm binding stability of lead candidates.
Main Results:
- Identification of 20 potential lead compounds with significant anticancer activity against MDA-MB-231 TNBC cell lines, with sensitivities ranging from 0.203 to 24.119 μM.
- Dapagliflozin (DB06292) was identified as a highly promising hit candidate based on its interaction profile with critical residues and validated through molecular dynamics simulations.
- The 200 ns molecular dynamics simulation confirmed the stable binding of Dapagliflozin to target proteins, reinforcing its potential as a therapeutic agent.
Conclusions:
- Repurposing FDA-approved drugs is a viable strategy for discovering novel IDO1/TDO inhibitors.
- Dapagliflozin demonstrates significant potential as a dual IDO1/TDO inhibitor for the management of triple-negative breast cancer.
- Further investigation into Dapagliflozin's efficacy and safety is warranted for its clinical application in TNBC treatment.
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