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Molecular Docking Studies and ADMET Predictions of Pyrimidine Coumarin Scaffolds as Potential IDO Inhibitors


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1 Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500085, TS, India
     

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Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic drug target for the treatment of cancer. IDO catalyzes the rate-limiting step of tryptophan degradation through kynurenine pathway. Reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to the immunosuppressive effects of IDO. Presence of IDO on dendritic cells in tumor-draining lymph nodes leading to the activation of T cells results in formation of immunosuppressive microenvironment for the survival of tumor cells, shows the importance of IDO as a novel anticancer immunotherapy drug target. Pyrimidine has the unique ability to act through many different mechanisms and its multiple biological activities make it an ideal therapeutic agent in treating cancer. In this effort directed towards the discovery of novel, potent IDO inhibitors for the treatment of cancer. In the present study a library of pyrimidine derivatives has been designed and evaluated for their anti-cancer activity targeting IDO using various computational approaches. Twenty new pyrimidine series of compounds were designed and docking studies were performed. All of them have found to be successfully docked inside the active binding domain of IDO with a binding energy in a range of -4.59 to - 9.53 Kcal/mol with predicted IC50 value range of 4.72 micro molar to 456.19 nano molar. On the other hand, calculated 2DQSAR molecular descriptor properties of the compounds showed promising ADME parameters and found to be in compliance with Lipinski's rule of five. Among all the twenty compounds tested, compound 14 (N'-(6-chloro-2-oxo-chromene-3-carbonyl)-4-(4-methoxyphenyl)-6-methyl-2-thioxo-3,4-dihydro-1H-pyrimidine-5-carbohydrazide) was found to be the best lead like molecule with a binding energy of -9.53 kcal/mol. Conclusively, newly designed compound 14 of the present study have shown promising anti-cancer potential worth considering for further evaluations.

Keywords

IDO Domain, Pyrimidine, Coumarin, Docking, ADME, Anti-Cancer.
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  • Molecular Docking Studies and ADMET Predictions of Pyrimidine Coumarin Scaffolds as Potential IDO Inhibitors

Abstract Views: 66  |  PDF Views: 5

Authors

Radhika Chelamalla
Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500085, TS, India
Ajitha Makula
Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500085, TS, India

Abstract


Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic drug target for the treatment of cancer. IDO catalyzes the rate-limiting step of tryptophan degradation through kynurenine pathway. Reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to the immunosuppressive effects of IDO. Presence of IDO on dendritic cells in tumor-draining lymph nodes leading to the activation of T cells results in formation of immunosuppressive microenvironment for the survival of tumor cells, shows the importance of IDO as a novel anticancer immunotherapy drug target. Pyrimidine has the unique ability to act through many different mechanisms and its multiple biological activities make it an ideal therapeutic agent in treating cancer. In this effort directed towards the discovery of novel, potent IDO inhibitors for the treatment of cancer. In the present study a library of pyrimidine derivatives has been designed and evaluated for their anti-cancer activity targeting IDO using various computational approaches. Twenty new pyrimidine series of compounds were designed and docking studies were performed. All of them have found to be successfully docked inside the active binding domain of IDO with a binding energy in a range of -4.59 to - 9.53 Kcal/mol with predicted IC50 value range of 4.72 micro molar to 456.19 nano molar. On the other hand, calculated 2DQSAR molecular descriptor properties of the compounds showed promising ADME parameters and found to be in compliance with Lipinski's rule of five. Among all the twenty compounds tested, compound 14 (N'-(6-chloro-2-oxo-chromene-3-carbonyl)-4-(4-methoxyphenyl)-6-methyl-2-thioxo-3,4-dihydro-1H-pyrimidine-5-carbohydrazide) was found to be the best lead like molecule with a binding energy of -9.53 kcal/mol. Conclusively, newly designed compound 14 of the present study have shown promising anti-cancer potential worth considering for further evaluations.

Keywords


IDO Domain, Pyrimidine, Coumarin, Docking, ADME, Anti-Cancer.