Molecular docking study of iclaprim derivatives with potential antineoplastic activity

Introduction: Dihydrofolate reductase (DHFR) is an ubiquitous enzyme in all cells. Inhibitors of this enzyme have been used for many years in numerous indications. Over the years, scientists have tried to improve existing therapy, so this have led to the discovery of iclaprim and propargyl-linked antifolates (PLA) whose characteristics can be used in the further design of DHFR inhibitors.

Material and Methods: This study aims to investigate the molecular docking of the 10 designed iclaprim derivatives into the human DHFR active site. All docking experiments were conducted using AutoDock Vina. The crystallographic structure of the human DHFR complex with a co-crystallized ligand, was taken from the Protein Data Bank database (PDB code: 3GHW).

Results: The designed compounds interacted with the active site of the enzyme, especially with the amino acid residues Phe31A, Phe34A and Asn64A. Lower binding energy occurs in chromium derivatives, from -9.4 to -8.4 kcal/mol, while compounds containing dimethoхybenzene showed higher binding energies from -8.1 to -7.6 kcal/mol. The designed compounds met the criteria for the Lipinski's rule. The presence of diaminopyrimidine ring and propargyl bond in the structure of the compound improves binding to the active site of the enzyme.