A comparative in silico study of noscapine, bosutinib, and the co-crystal ligand (DHHE) of 3B99 to investigate their interaction with prostacyclin synthase

Abstract

Prostacyclin synthase (PGIS), a heme-containing cytochrome P450 enzyme located in the endoplasmic reticulum membrane, catalyzes the isomerization of prostaglandin H2 (PGH2) into prostacyclin, an essential mediator of vascular homeostasis. The present work investigates the interaction of prostacyclin synthase (PDB ID: 3B99) with noscapine (Nos), bosutinib (Bos), and the co-crystal ligand (DHHE) through molecular docking, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. Molecular docking revealed binding affinities of − 7.9, − 7.3, and − 6.2 kcal/mol for Nos, Bos, and DHHE, respectively, with Nos exhibiting the strongest interactions through hydrogen bonds and hydrophobic contacts involving residues such as Leu101, Ala335, and Leu336. DFT calculations indicated that DHHE displayed the highest stability with the largest HOMO–LUMO energy gap (− 0.18 Hartree), while Bos exhibited the highest chemical reactivity. MD simulations over 500 ns highlighted the dynamic stability of these complexes, with Bos showing minimal structural deviations (RMSD: 0.19–0.34 nm) and Nos demonstrating significant Van der Waals stabilization. Principal component analysis indicated that ligand binding induces conformational flexibility in PGIS, with Bos complexes demonstrating enhanced compactness and stability. The interaction energy analysis reveals that Bos exhibits the strongest binding affinity to the 3B99 target, with the most favorable Coulombic (− 47.86 ± 3.6 kJ/mol) and Lennard–Jones interactions (− 203.558 ± 4.9 kJ/mol), resulting in the lowest total interaction energy (− 251.418 kJ/mol), compared to 3B99-Nos and 3B99-DHHE.

Graphical abstract