Understanding the mode of inhibition and molecular interaction of taxifolin with human adenosine deaminase

Abstract

Adenosine deaminase is a zinc⁺² dependent key enzyme of purine metabolism which irreversibly converts adenosine to inosine and form ammonia. Overexpression of adenosine deaminase has been linked to a variety of pathophysiological conditions such as atherosclerosis, hypertension, and diabetes. In the case of a cell-mediated immune response, ADA is thought to be a marker, particularly in type II diabetes. Deoxycoformycin is the most potent ADA inhibitor that has been discovered so far, but it has several drawbacks, including being toxic and having poor pharmacokinetics. Taxifolin, a flavonoid derived from plants, was discovered to be a potent inhibitor of the human ADA (hADA) enzyme in the current study. Taxifolin bound at the active site of human ADA and showed fifty percent inhibition at a concentration of 400 µM against the enzyme. To better understand the interactions between taxifolin and human ADA, docking and molecular dynamic simulations were performed. In-silico studies using autodock revealed that taxifolin bound in the active site of human ADA with a binding energy of −7.4 kcal mol ⁻¹ and a theoretical Ki of 3.7 uM. Comparative analysis indicated that taxifolin and deoxycoformycin share a common binding space in the active site of human ADA and inhibit its catalytic activity similarly. The work emphasises the need of employing taxifolin as a lead chemical in order to produce a more precise and effective inhibitor of the human ADA enzyme with therapeutic potential.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human adenosine deaminase
• molecular docking
• MD simulation
• inhibition studies
• enzyme activity and taxifolin

Acknowledgement

Corresponding Author thanks to ICMR for financial assistance under a regular grant.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Indian Council of Medical Research (ICMR), Govt. of India.