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A new lipid-lowering drug in the making

Amruta Morone

Researchers at the Central Drug Research Insitute (CDRI), Lucknow, recently synethesized a class of chemical compounds which have strong anti-oxidant and anti-dyslipidemic activity, adding to the arsenal of potential drugs targeting lifestyle disorders like obesity and diabetes.

A new lipid-lowering drug in the making
A new lipid-lowering drug in the making  

The famous Turkish cardiothoracic surgeon Mehmet Öz once said, Your genetics load the gun. Your lifestyle pulls the trigger.” Our sedentary and stressful lifestyle may be responsible for the rise of cardiovascular diseases, diabetes, obesity, increased blood pressure, lipid imbalance and more. In a recent study led by Amit Gupta and Anil Saxena at the Central Drug Research Institute, Lucknow, researchers synthesized a novel class of chemical moiety with anti-oxidant activity, which counteracts the imbalance of lipids, especially cholesterol, in the blood.

Dyslipidemia is a metabolic disorder characterised by an increase in total cholesterol, low-density lipoproteins (LDLs) (also called bad cholesterol) and triglyceride levels, along with a drop in high-density lipoproteins (HDLs) (also called good cholesterol). Elevated LDL-cholesterol levels alone or in combination with oxidative stress lead to increased risk of cardiovascular diseases and diabetes. 

The current armoury of cholesterol-lowering drugs like statins, niacin derivatives, etc. often exhibit side-effects. This calls for discovering new potential cholesterol-lowering molecules, which can correct lipid imbalance and reduce high glucose levels (hyperglycemia) to treat various metabolic diseases and lifestyle disorders. 

In view of this, the researchers synthesised a novel chemical moiety, oxopropylindole hydrazone, which can serve as an excellent lead compound for future drug design efforts. It was previously known that the oxopropylindole ring of tryptophan and hydrazone are used separately as therapeutic options for different metabolic diseases. Therefore, we thought of integrating both moieties to synthesise a single hybrid molecule, possessing combined properties,” says Gupta. 

In normal conditions, cell repair or cell death events trigger lipid oxidation. However, stress or lifestyle-associated metabolic disorders release free radicals that not only oxidise lipids but also damage other cells, which aggravates the problem of lipid imbalance. 

Therefore, the researchers designed and synthesised twelve derivatives of the hybrid molecule and screened for anti-oxidant, anti-hyperglycemic and anti-dyslipidemic activity. To test these activities, the researchers injected mice with Triton, a chemical agent, to induce dyslipidemia and then administered the derivatives. Interestingly, two of the twelve derivatives exhibited good anti-oxidant, anti-hyperglycemic, anti-adipogenic activity and were able to reduce LDL oxidation, triglyceride and total cholesterol levels. 

However, the researchers didn’t stop at identifying the chemical derivatives with the best anti-dyslipidemic activity. The real challenge was finding the important interactions responsible for the biological activity,” says Gupta, In order to comprehend this, knowledge about the 3D structure of the target and its interaction with different functional groups of drugs is important.” 

Such structure-based drug design is done through molecular docking. Molecular docking predicts the binding orientation of drug molecules to their target, which in turn envisages the binding affinity and activity of drug molecules. 

The in vivo experiments revealed that the administration of the synthesised derivatives led to a significant reduction in cholesterol level, lipid accumulation and blood glucose levels and improvement in lipoprotein lipase activity. The binding of these derivatives at lipoprotein lipase active site was corroborated through computational molecular docking. The reduction in cholesterol and glucose levels were comparable to standard drugs Gemfibrozil and Metformin. 

Cardiovascular diseases are the major cause of death in India and India is also foreseen to be the diabetes capital’ of the world according to the World Health Organization and Diabetes Foundation (India). The study has definitely provided an in vitro and in vivo proof of concept that a single molecule possesses combined activities (unlike that in other drugs), and hence can be used for the treatment of multiple lifestyle disorders,” says Sanjeev Giri, Senior Director, Aurigene Discovery Technologies, Hyderabad.

The initial results are encouraging and the study will make a good impact once optimisation, safety assessment, toxicological studies, and risk-benefit are evaluated,” adds Giri. This study adds to the list of promising drug targets for the treatment of lifestyle disorders, which are predicted to rise in the coming decades.


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