Discovering natural product inhibitors of Cryptococcus neoformans farnesyltransferase through data-fusion based screening and molecular dynamics

Cryptococcus neoformans is an opportunistic human fungal pathogen that can cause severe respiratory and neurological infections. There are limited antifungals that can treat C. neoformans infections, and resistance is rising, creating an urgent need for new drugs. The enzyme farnesyltransferase (PFT) is essential for the survival of C. neoformans. In this research, natural products targeting PFT were investigated using molecular modeling techniques. A data-fusion-based virtual screening protocol was used to evaluate 765,708 natural compounds against the target protein. The promising hits from this screening were further analyzed using extra-precision docking, pharmacokinetic profiling, and toxicology assessments. The ten most promising candidates were identified and subsequently subjected to further analysis using molecular dynamics simulations combined with MM/PBSA free energy calculations. Among all screened compounds, ligand A exhibited the strongest binding affinity towards PFT, with a docking score of − 10.55 kcal/mol. Furthermore, pharmacokinetic profiling, drug-likeness evaluation, and toxicity analysis indicate that ligand A is non-carcinogenic and capable of crossing the blood–brain barrier, underscoring its potential as a promising therapeutic candidate. Molecular dynamics simulations and MM/PBSA calculations confirmed the stability of the ligand A-PFT complex, with a favorable binding free energy of − 46.15 kcal/mol. Although computational results are promising, further in vitro and in vivo studies are needed to advance this potential inhibitor as a therapeutic drug.