Natural Products in Precision Cryptococcal Meningitis: Phytochemical Screening of Glycyrrhiza glabra Plant against Cryptococcus neoformans Farnesyltransferase (FTase).

Cryptococcus neoformans, the most opportunistic fungal pathogen, causes cryptococcal meningitis. Based on molecular docking and ADME/toxicity analysis, the top two lead compounds selected from a screening of 5,807 phytochemical compounds from 29 medicinal plants were CID_8299 and CID_71346280, with docking scores of -5.786 and -6.078 Kcal/mol, respectively, indicating stronger binding affinities than the control ligand CID_3365 (fluconazole), which scored -4.2 kcal/mol. Both the control ligand and lead compounds bind at the common active site of protein by interacting with common amino acid residues (HIS97, GLN408, PHE93, and TRP94). Then, molecular docking results were verified using post-docking MM-GBSA where CID_8299 and CID_71346280 had negative binding free energies of -19.81 and -0.27 Kcal/mol respectively. Through MD simulation (100 ns) these two lead compounds were reassessed and several post-dynamics analyses revealed that CID_8299 exhibited 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 blood-brain barrier which makes it unbeatable in treating neurological disease caused by C. neoformans and may potentially block FTase protein's activity in C. neoformans inhibiting post-translational lipidation of key signal transduction proteins.