The pathology of Parkinson’s is the degeneration of cells in the mid brain that otherwise regulate the release of dopamine.  The body is thus supplemented with L-DOPA, the precursor of dopamine, which also has the potential to cross the blood brain barrier. However, innate DOPA decarboxylase converts the L-DOPA into dopamine while in the peripheral system. The NBI strategic innovation team consists of Dr Parthasarathi Ramakrishnan, Dr Aashish Gambhir and Dr Kamireddy Kiran.

The body thus remains dopamine deficient since the molecule by itself cannot cross the blood brain barrier. It is observed that the role of enzymes such as DOPA decarboxylase is critical to ensure L-DOPA is not converted to dopamine in the peripheral system. Molecules that can inhibit DOPA carboxylase are thus essential to manage Parkinson’s. NBI in collaboration with CSIR-IITR used advanced molecular docking techniques to predict the activity of over 10,000 molecules derived from natural sources. In addition to predictive active receptor binding data, the molecular docking technique was also used to predict the ability of the molecules to cross the blood brain barrier. With this systematic approach, an approximate 10 compounds were short listed to take forward to the next level of screening and identification of the ideal formulation.

In vitro screening of DDC inhibition potential: The shortlisted molecules from in silico screening were primarily subjected to in vitro cytotoxicity testing at NIPER. The screening was carried out on multiple cell lines. Based on the non-toxic nature of 3 active compounds even at high concentrations, they were selected to estimate their DDC inhibition potential. A dose response curve was observed with increasing concentrations of the active molecules on the enzyme. A 100% inhibition was observed with doses as low as 1200 – 1300 µg/ml. The number of molecules after completion of the in vitro assay was shortlisted to 3. The next stage of evaluating the compound was through its efficacy in human subjects.

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