Erythrinin C, From The Root of Pueraria Peduncularis, is a Potential Antagonist Against DHODH, A Therapeutic Target in Acute Myeloid Leukemia: An In Silico Study

Acute myeloid leukaemia (AML) is the second most common form of leukaemia with an annual incidence of 3.6 per 100,000 adults in the United States. A 5-year survival rate of a person with AML is less than 50%. Myeloid leukemogenesis has been reported to arise by a differentiation arrest at early progenitor stage of hematopoietic maturation of the bone marrow; this has led researchers to identify the human dihydroorotate dehydrogenase (DHODH) to be a therapeutic target in the differentiation therapy for AML. Several inhibitors of DHODH have been developed; however only a few have reached clinical trials of which include Brequinar, a strong DHODH inhibitor. Brequinar has reached a phase 2 clinical trials, however, several complication and toxicities have been reported in phase 1 clinical trials in patients with solid tumours. This ranges from myelosupression, thrombocytopenia, nausea, vomiting, skin rashes, mucositis, and this limit its use in AML. In view of this, research is focused on identifying potent DHODH inhibitors with little or no toxic effect that can be used in the differentiation therapy of AML.

Pueraria peduncularis belongs to the Leguminosae family and it is widely distributed in some parts of China, India, Pakistan, Nepal and Burma. A recent study has accessed and reported that flavonoids from root of Pueraria peduncularis have anti-tumour effects against cancer cell lines.

The aim of this study was to analyse flavonoids from (plant source) root of Pueraria peduncularis for their DHODH inhibitory potential via computational docking studies. For this, four (4) flavonoids (phytochemicals), as well as the DHODH co-crystallized inhibitor, BAY 2402234 which serve as the standard in the present study, were retrieved from the literature and screened for their inhibitory effects on DHODH. Erythrinin C was the lead compound with a binding energy of -11.395kcal/mol. Computational docking and scoring analysis were performed using Lead Finder tool implemented in Flare software of Cresset Inc. (2019, Litlington, UK). The target was validated to ensure that the right target was used for this analysis.