In silico identification and characterization of potent laccase inhibitors against Cryptococcus neoformans: A multi-scale computational study

Authors

  • Muharib Alruwaili Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia Author
  • Sonia Younas (1)Centre for Immunology and Infection (C2i), Hong Kong Science and Technology Park, Hong Kong, SAR China (2)HKU-Pasteur Research Pole, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China Author
  • Muhammad Umer Khan Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54590, Pakistan Author
  • Hammad Saleem Institute of Pharmaceutical Sciences (IPS), University of Veterinary & Animal Sciences (UVAS), Lahore, Pakistan Author
  • Yasir Alruwaili (1)Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia (2)Sustainable Development Research and Innovation Center, Deanship of Graduate Studies and Scientific Research, Jouf University, Sakaka 72388, Saudi Arabia Author
  • Abualgasim Elgaili Abdalla Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia Author
  • Bi Bi Zainab Mazhari Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Qurayyat 75911, Saudi Arabia Author
  • Khalid Abosalif Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia Author
  • Hasan Ejaz Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia Author

DOI:

https://doi.org/10.35495/

Keywords:

C. neoformans, Ellagic acid, Laccase inhibitor, Molecular docking, ADMET, Antifungal

Abstract

Cryptococcus neoformans is an opportunistic fungal pathogen, especially affecting individuals with weakened
immune systems. Laccase enzymes are pivotal in its pathogenicity, making them promising targets for therapeutic
intervention. This study aims to identify and characterize potent laccase inhibitors against C. neoformans using
advanced in-silico analysis. The laccase protein (UniProt ID: Q55P57) was retrieved via AlphaFold and validated
with ProCheck. Pharmacophore-based virtual screening (PBVS) identified 19 potential inhibitors, which were
docked using CB-Dock2. The top six compound’s pharmacokinetic properties were assessed using SwissADME,
PKCSM, and StopTox. Bioactivity was predicted via SwissTargetPrediction. Density Functional Theory (DFT)
calculations were conducted using Gauss view 5.0.8. The validated 3D structure of the target protein Q55P57
demonstrated high quality, with 86.5% of residues in favored regions. The molecular docking revealed that L-11
exhibited the highest binding affinity (-13.2 kcal/mol), forming crucial interactions within the active site. L-11
displayed favorable physicochemical properties, including high lipophilicity and good Caco2 permeability,
positioning it as a strong candidate for therapeutic development. Toxicity predictions indicated non-toxicity for
acute inhalation and oral exposure, while bioactivity analysis highlighted its broad target interactions. DFT
analysis demonstrated L-11's enhanced reactivity due to its high dipole moment and low HOMO-LUMO energy
gap. The identification of L-11 (8-[4-[9,9-Dimethyl-7-(2,3,4,5,6,7,8,9,10-nonahydroxypyren-1-yl)fluoren-2-
yl]phenyl]pyrene-1,2,3,4,5,6,7,9,10-nonol) as a potent inhibitor of C. neoformans laccase represents a novel
approach to antifungal drug discovery, marking a significant step to combat fungal infections and a way forward
to perform in-vitro and in-vivo studies and ultimately its clinical application.

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Published

07-03-2025

Issue

Online First (Future Issue)

Section

Articles