Discovery of Novel Antifungal Agents from Polygonatum odoratum Targeting 14-Alpha Demethylase Enzyme for the Treatment of Black Fungus (Mucormycosis)

Significant rise in mucormycosis cases during the COVID-19 pandemic was observed in the year 2021, when the majority of infected cases were reported in country India. Mucormycosis is an opportunistic angio-invasive fungal infection with a high mortality rate. Since the onset of COVID19, more than 8,800 Mucormycosis cases have been documented in country India. 14-alpha demethylase enzyme (CYP51) played a significant role in the fungal sterol biosynthesis and maintaining fungal cell membrane integrity. Hence CYP51 was selected as the target protein for discovering antifungal drugs and served as the molecular target due to its significance. The present study investigates the potential antifungal compounds targeting mucormycosis through computational biology. A database of 1612 chemical molecules were selected for testing toxicity with the help of ADMET analysis using a webserver known as SwissADME. Among 1612 molecules tested, 05 molecules displayed both safety and efficacy during the ADMET test, which were further explored as ligand molecules to evaluate their binding affinity with target protein 14-alpha demethylase enzyme (CYP51). 05 ligand molecules and target protein CYP51 were prepared for the molecular docking process by applying UCSF Chimera software integrated with the AutoDock vina package. Molecular docking of 05 ligand molecules with the active site of target protein CYP51 was performed through PyRx software. All the 05 ligand molecules (CHEMBL1094947, Glycyrrhiza flavonol A, Lachnoisoflavones A, Cyanate ester of tropylium cation, and cyclokievitone displayed better docking results than standard drug Amphotericin B for the target protein CYP51. Among these 05 ligand molecules, phytocompound CHEMBL1094947 extracted from the plant Polygonatum odoratum displayed the docking or binding score i.e. -9.9 $\mathrm{kcal} / \mathrm{mol}$ with the target protein CYP51. Hence CHEMBL1094947 can be further explored as an antifungal drug through in-vitro studies.