Molecular docking and ADMET prediction of compounds obtained from Stephania dinklagei roots as inhibitors of NMDA receptor

Stephania dinklagei root is known in Nigeria for its medicinal properties, especially its role in the nervous system. N-methyl-D-aspartate receptor (NMDAR) has been linked to various neurological disorders. The potential of compounds obtained from S. dinklagei roots to inhibit the function of NMDAR is thus the focus of this in silico study. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze compounds in S. dinklagei roots. Molecular docking against GluN2B NMDAR (PDB ID: 7SAD) was done using AutoDock Vina, while ADMET studies were carried out using SwissADME and ProTox 3.0 webservers. Memantine was used as the standard compound. Sixteen compounds were detected in the sub-fraction of S. dinklagei roots, with 75% having binding affinities > memantine (-5.3 kcal/mol). Geijerone, 7-(4,8-dimethylnona-3,7-dien-1-yl)-2,4',5,5',7',10-hexahydroxy-2,2'-dimethyl-1,2,3,4,9',10'-hexahydro-[1,1'-bianthracene]-4,9',10'-trione (DHBT) and alpha,beta-Dihydroxanthohumol (αβD), exhibited the highest binding affinities: -9.5, -9.3 and -7.0 respectively. The three compounds interacted with the same amino acid residues as memantine. Geijerone and αβD had 0 Lipinski, Ghose, Veber and Egan violations. They also have a bioavailability score of 0.55, are both soluble, and have a high gastrointestinal (GI) absorption profile. The three compounds are not Pgp substrates, and only geijerone was predicted to be a blood-brain barrier (BBB) permeant. DHBT and geijerone do not inhibit cytochrome P450 (CYP) enzymes; however, αβD inhibits all except CYP2C19. LogKp values of geijerone and αβD, -5.26 and -5.01 cm/s respectively, are comparable to memantine (-5.06 cm/s). The compounds belong to toxicity class 3 – 5. DHBT and αβD were predicted to be immunotoxic, respectively carcinogenic and nephrotoxic. Geijerone had a better binding affinity, similar drug-likeness, and ADME properties as memantine, but with a lower toxicity profile, and can therefore be further explored as an inhibitor of NMDAR.