Molecular docking and dynamic simulation studies evidenced plausible immunotherapeutic anticancer property by Withaferin A targeting indoleamine 2,3-dioxygenase

Abstract

Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic drug target for the treatment of cancer characterized by pathological immune suppression. IDO catalyzes the rate-limiting step of tryptophan degradation along the 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 dentritic cells in tumor-draining lymph nodes leading to the activation of T cells toward forming immunosuppressive microenvironment for the survival of tumor cells has confirmed the importance of IDO as a promising novel anticancer immunotherapy drug target. On the other hand, Withaferin A (WA) - active constituent of Withania Somnifera ayurvedic herb has shown to be having a wide range of targeted anticancer properties. In the present study conducted here is an attempt to explore the potential of WA in attenuating IDO for immunotherapeutic tumor arresting activity and to elucidate the underlying mode of action in a computational approach. Our docking and molecular dynamic simulation results predict high binding affinity of the ligand to the receptor with up to -11.51 kcal/mol of energy and 3.63 nM of IC50 value. Further, de novo molecular dynamic simulations predicted stable ligand interactions with critically important residues SER167; ARG231; LYS377, and heme moiety involved in IDO's activity. Conclusively, our results strongly suggest WA as a valuable small ligand molecule with strong binding affinity toward IDO.

Identification of potential drugs targeting L,L‐diaminopimelate aminotransferase of Chlamydia trachomatis: An integrative pharmacoinformatics approach

“…Ligand torsions dynamics during the production run was analyzed by Ligand torsion plot option of Schrödinger suite. This plot demonstrates the number of rotatable bonds present in the ligand and the degree of its freedom along with the energy consumed for this rotation . For NSC_152451 and NSC_41500, a total of 10 rotatable bonds were observed.…”

Insights from molecular modeling, docking and simulation of imidazole nucleus containing chalcones with EGFR kinase domain for improved binding function

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Potential Anticancer Properties and Mechanisms of Action of Withanolides

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