Enzyme-substrate interactions in orotate-mimetic OPRT inhibitor complexes: a QM/MM analysis

Area of Science:

• Biochemistry
• Enzymology
• Computational Chemistry

Background:

• Orotate phosphoribosyltransferase (OPRT) is crucial for nucleotide biosynthesis.
• OPRT inhibition is a therapeutic strategy for cancer, tuberculosis, and malaria.

Purpose of the Study:

• To investigate the competitive binding of orotic acid (OA) and OA-mimetic inhibitors to OPRT.
• To elucidate the molecular interactions driving OPRT inhibition using computational methods.

Main Methods:

• Quantum Mechanics/Molecular Mechanics (QM/MM) framework applied to Saccharomyces cerevisiae OPRT.
• Analysis of protein-ligand interactions, including binding energetics and hydrogen bonding networks.

Main Results:

• 4-Hydroxy-6-methylpyridin-2(1H)one demonstrated the highest inhibitory activity among tested OA-mimetic compounds.
• The inhibitor forms strong hydrogen bonds and hydrophobic contacts within the OPRT binding site.
• Bridging water molecules and π-electron interactions contribute to stable ligand binding.

Conclusions:

• The study provides atomic-level insights into OPRT inhibition mechanisms.
• 4-Hydroxy-6-methylpyridin-2(1H)one is a promising lead compound for developing novel therapeutic agents targeting OPRT.