Abstract
Background: The mortality and morbidity rates in patients caused by fungi are extremely
high. 3-4 % of species of fungi like Candida and Aspergillus are responsible for >99%
of invasive fungal infections.
Aim: The goal of the current work was to use several In-silico methods, such as Pharmacophore
modeling and 3D-QSAR, to design New chemical entities (NCEs) that have antifungal activity.
Materials & Methods: A dataset of 40 Psoralen derivatives was taken from available literature,
and then, the pharmacophore hypothesis and 3D-QSAR model development were generated
using Schrodinger 2023-1 software. After designing a library of 36 compounds, they were subjected
to ADMET prediction. Screened compounds from the ADMET study were docked with
14 alpha demethylase CYP51 (PDB ID: 3LD6) using Schrödinger software. Molecular dynamics
(MD) simulation studies were performed on PDB-3LD6 using Desmond-v7.2.
Results & Discussion: The top-ranked hypothesis, AHRRR_1, was taken into consideration
when designing the library of potential NCEs.In order to check the drug likeliness of the compounds,
all 36 designed NCEs were subjected to ADMET prediction using the QikProp tool.
The majority of compounds have a good partition coefficient index (less than five). Qplog
HERG value was found to be less, making them safer and less toxic. C- 4, 6, 9, 13, 15, 22, 24,
27, 31, and 33 have shown compliance with Lipinski’s rule with zero violations. Compounds
C-9, C-13, C-22, C-24, and C-27 have shown better docking scores than the standard Ketoconazole.
Compounds C-9, 24, and 27 have shown a greater number of hydrophobic and hydrogen
bond interactions in comparison with the other compounds. Compounds 9, 24, and 27 showed
good stability after 100ns molecular simulation simulations.
Conclusion: In the current work, the application of insilico methods such as pharmacophore
hypothesis, 3D QSAR, ADMET study, docking, and simulation studies have helped to optimize
Psoralen pharmacophore for potential antifungal activity. Therefore, the outcomes of the present
study could provide insights into the discovery of new potential alpha demethylase inhibitors
with improved selectivity and activity against fungal infections.
Graphical Abstract
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