Natural Products in Precision Neurological Disease (Cryptococcal Meningitis): Structure‐Based Phytochemical Screening of <i>Glycyrrhiza glabra</i> Plant Against <i>Cryptococcus neoformans</i> Farnesyltransferase (FTase)

Cryptococcus neoformans causes cryptococcal meningitis, which is lethal to immune-compromised people, especially AIDS patients. This study employed diverse in silico techniques to find the best phytochemical to block farnesyltransferase (FTase). Based on molecular docking, the top two compounds selected from a screening of 5807 phytochemical compounds from 29 medicinal plants were CID_8299 (hydroxyacetone) and CID_71346280 (1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one), with docking scores of -5.786 and -0.078 kcal/mol, respectively, indicating stronger binding affinities than the control CID_3365 (fluconazole), which scored -4.2 kcal/mol. The control and lead compounds bind at the common active site of protein by interacting with common amino acid residues (HIS97, GLN408, PHE93, and TRP94). Post-docking MM-GBSA verified docking score where CID_8299 and CID_71346280 had negative binding free energies of -19.81 and -0.27 kcal/mol, respectively. These two lead compounds were reassessed through molecular dynamics simulation (100 ns), and several post-dynamics analyses were conducted. CID_71346280, 8299, and 3365 (control) showed average RSMD values of 3.17, 1.904, and 2.08; average root mean square fluctuation values of 1.167, 0.886, and 1.028 Å; average radius of gyration values of 5.13, 1.58, and 3.54 Å; average solvent accessible surface area values of 121.16, 3.51, and 183.81 Ų; average H-bond values of 466.05, 470.84, and 456.84 Å, respectively. The results revealed that CID_8299 had the highest stability and consistent interaction with the target protein throughout the simulation period. According to the toxicity analysis, CID_8299, which is found in the Glycyrrhiza glabra plant, can also cross the BBB, which makes it unbeatable in treating neuro-disease caused by C. neoformans and may potentially block FTase protein's activity inhibiting post-translational lipidation of essential signal transduction protein.