Current medicinal chemistry · 2026
Pharmacological Modulation of the Tryptophan-kynurenine Pathway by the Intervention of Indoleamine 2,3-dioxygenase 2 (IDO2) and Kynureninase (KYNU) in Ovarian Cancer.
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Velmurugan Pavithra, Parsanathan Rajesh, Shankari Gopalakrishnan, Ganapathi Haema, Moovarkumudalvan Balasubramanian, Singh Abhimanyu K, Saravanan Suresh Kumar, Rajamanikandan Sundararaj, Subramanyam Veni
Аннотация
INTRODUCTION: The tryptophan (TRP)-serotonin pathway is disrupted and redirected towards kynurenine by the action of indoleamine 2,3-dioxygenase 2 (IDO2) and kynureninase (KYNU). In ovarian cancer, concurrent kynurenine activation encourages tumor growth and immune evasion. The investigation of phytochemicals has focused on identifying therapeutic targets in ovarian cancer.
METHODS: Gene expression, survival plots, and comparisons of correlated genes were computed to obtain holistic insights into the identified targets. A Kaplan-Meier analysis was performed to examine the survival patterns of IDO1 and KYNU targets. Molecular docking was performed to determine the binding affinity of ligands, and the Desmond module of Schrodinger was used to confirm the docking scores through simulation. Physiochemical and ADMET properties were assessed using SwissADME and pkCSM. Electronic effects and stability were further confirmed using Gaussian software.
RESULTS: Protein-protein interactions of TRP metabolism revealed IDO2 and KYNU as potential targets involved in pathway diversion. The comparison of mutated and non-mutated targets showed no significant difference, reflecting the tumor's heterogeneity and the limited number of mutated samples. Molecular docking studies of 368 phytochemicals from six sources, reported to have anti-ovarian cancer properties, revealed 11 phytochemicals with higher binding affinities of -9.7 kcal/mol for IDO2 and -9.4 kcal/mol for KYNU. The interaction between the target and ligand was confirmed by molecular dynamics simulation using the Desmond module V3 of Schrödinger software. The stability and reactivity of phytochemicals were assessed using HOMO-LUMO and energy gap calculations. The highest electron stability was shown in 24MC (6.95 eV) and C24β (6.93 eV) compared with controls. The identified phytochemicals were further evaluated for their ADMET properties to refine therapeutic hit compounds. Compounds, such as Hemanthidine (HAT), Ergometrine (ERG), Tazettine (TZT), Tenatoprazole (TU-199), Rucaparib (CO-338), and Nicotinylalanine (NAL), have been reported to improve drug absorption.
DISCUSSION: By altering the ovarian cancer microenvironment, targeting immunometabolism with a clinically relevant approach improves therapeutic efficacy. Target expression clarifies the immune-rich tumor microenvironment rather than the actual tumor growth. Higher-binding-affinity compounds demonstrate high electronic stability in energy estimates as well as improved drug availability in pharmacokinetic investigations. However, this finding remains a computational approach and requires experimental validation.
CONCLUSION: This computational study identifies suitable hit compounds for targeting TRP depletion, expanding the scope for subsequent in vitro and in vivo exploration to expedite drug discovery.
METHODS: Gene expression, survival plots, and comparisons of correlated genes were computed to obtain holistic insights into the identified targets. A Kaplan-Meier analysis was performed to examine the survival patterns of IDO1 and KYNU targets. Molecular docking was performed to determine the binding affinity of ligands, and the Desmond module of Schrodinger was used to confirm the docking scores through simulation. Physiochemical and ADMET properties were assessed using SwissADME and pkCSM. Electronic effects and stability were further confirmed using Gaussian software.
RESULTS: Protein-protein interactions of TRP metabolism revealed IDO2 and KYNU as potential targets involved in pathway diversion. The comparison of mutated and non-mutated targets showed no significant difference, reflecting the tumor's heterogeneity and the limited number of mutated samples. Molecular docking studies of 368 phytochemicals from six sources, reported to have anti-ovarian cancer properties, revealed 11 phytochemicals with higher binding affinities of -9.7 kcal/mol for IDO2 and -9.4 kcal/mol for KYNU. The interaction between the target and ligand was confirmed by molecular dynamics simulation using the Desmond module V3 of Schrödinger software. The stability and reactivity of phytochemicals were assessed using HOMO-LUMO and energy gap calculations. The highest electron stability was shown in 24MC (6.95 eV) and C24β (6.93 eV) compared with controls. The identified phytochemicals were further evaluated for their ADMET properties to refine therapeutic hit compounds. Compounds, such as Hemanthidine (HAT), Ergometrine (ERG), Tazettine (TZT), Tenatoprazole (TU-199), Rucaparib (CO-338), and Nicotinylalanine (NAL), have been reported to improve drug absorption.
DISCUSSION: By altering the ovarian cancer microenvironment, targeting immunometabolism with a clinically relevant approach improves therapeutic efficacy. Target expression clarifies the immune-rich tumor microenvironment rather than the actual tumor growth. Higher-binding-affinity compounds demonstrate high electronic stability in energy estimates as well as improved drug availability in pharmacokinetic investigations. However, this finding remains a computational approach and requires experimental validation.
CONCLUSION: This computational study identifies suitable hit compounds for targeting TRP depletion, expanding the scope for subsequent in vitro and in vivo exploration to expedite drug discovery.