Identification of Small molecule inhibitors of Nogo 66 Receptors to enhance CNS regeneration after neuropathic damage

Abstract

Diabetic Neuropathy is a complication were due to increase in blood sugar levels the neurons loss their function and gets damaged. India ranks 2nd next to china, in Diabetes as well Gujarat has maximum diabetics among all the states of India. So to assess the prevalence of Diabetic neuropathy in Bhavnagar district of West Gujarat demographic survey was conducted by stratified random sampling. It was observed that about 16% of population were Diabetics where maximum of them were of 55 – 64 age group.70.59 % of females were affected by neuropathy and 16.33 % of males were affected with neuropathy. Due to their lifestyle and being housewives female subjects were more prone to diabetes. Severity of neuropathic complications evaluated based on three types of scoring system MDNS, DNS and NSS. From which it was observed that majority of the females had neuropathic symptoms. In neuropathy the neuron gets injured by which the myelin and axon get damaged in the neuron. Such neurons have regenerative potential but it is limited in CNS compared to PNS due to many reason. Presence of inhibitory proteins inhibits the regeneration of CNS neurons by Nogo pathway where these proteins binds to Nogo receptor. So with the help of neuroinformatics small molecules that have neuroprotective and neurite outgrowth property were selected by in silico. A library of phytochemicals was prepared on which protein ligand docking study was done using Autodock Vina, Blind Docking server and iGemdock. The successfully docked molecules were further taken forward for pharmacokinetics study using online web server SwissADME and Molinspiration. Only 11 molecules of which Bismethoxycurcumin, Theophylline, Kaempferol and isorhamnetin were BBB permeant while Curcumin, Demethoxycurcumin, Naringenin, Pelargonidin, Catechin, Epicatechin and Hesperetin don’t cross BBB. The successfully docked and ADMET passed molecules were taken forward for pharmacophore modelling. Pharmacophore modelling was done using Pharmagist webserver. The molecules Bismethoxycurcumin, Theophylline, Kaempferol and Isorhamnetin cross BBB were selected and the score was obtained 15.678 and Curcumin , Demethoxycurcumin, Naringenin, Pelargonidin, Catechin, Epicatechin and Hesperetin that cannot cross BBB had score 29.678. The remaining 11 molecules pharmacophore modelling was done of which those molecules that cross BBB can enhance CNS regeneration while the others don’t cross BBB hence it may be possible that those molecule may enhance PNS regeneration.