Unveiling Moroccan Nature's Arsenal: A Computational Molecular Docking, Density Functional Theory, and Molecular Dynamics Study of Natural Compounds against Drug-Resistant Fungal Infections

Abstract

Candida albicans and Aspergillus fumigatus are recognized as significant fungal pathogens, responsible for various human infections. The rapid emergence of drug-resistant strains among these fungi requires the identification and development of innovative antifungal therapies. We undertook a comprehensive screening of 297 naturally occurring compounds to address this challenge. Using computational docking techniques, we systematically analyzed the binding affinity of each compound to key proteins from Candida albicans (PDB ID: 1EAG) and Aspergillus fumigatus (PDB ID: 3DJE). This rigorous in silico examination aimed to unveil compounds that could potentially inhibit the activity of these fungal infections. This was followed by an ADMET analysis of the top-ranked compound, providing valuable insights into the pharmacokinetic properties and potential toxicological profiles. To further validate our findings, the molecular reactivity and stability were computed using the DFT calculation and molecular dynamics simulation, providing a deeper understanding of the stability and behavior of the top-ranking compounds in a biological environment. The outcomes of our study identified a subset of natural compounds that, based on our analysis, demonstrate notable potential as antifungal candidates. With further experimental validation, these compounds could pave the way for new therapeutic strategies against drug-resistant fungal pathogens.

Keywords: ADME-Toxicity; Density Functional Theory; antifungal activity; dynamics simulation; molecular docking.

Figure 1

The superimposed poses of the original (gray) and redocked (green) FAD and A70 ligands inside the 1EAG and 3DJE receptor pockets.

Figure 2

Two- and three-dimensional visualization of interactions between the compounds L1, the reference drug “fluconazole”, and the 1EAG protein target.

Figure 3

Two- and three-dimensional visualization of interactions between the compounds L13, the reference drug “fluconazole”, and the 3DJE protein target.

Figure 4

The predicted bioavailability radar of compounds L1 and L13.

Figure 5

Frontier molecular orbitals (FMOs) for the studied compounds L1 and L13.

Figure 6

Electrostatic potential mapping for the compounds L13 and L1.

Figure 7

The RMSD and RMSF plots of both complexes L1-1EAG and L13-3DJE.

Figure 8

Protein–ligand histogram and number of contacts between compounds L1 and 1EAG protein.

Figure 9

Protein–ligand histogram and number of contacts between compounds L13 and 3DJE protein.

Figure 10

Three-dimensional representation of target proteins with well-defined active sites for protein–ligand–drug interaction.