Intramolecular Versus Intermolecular Bonding in Drug Gemcitabine and Nucleobases: A Computational Study

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug-nucleobase interactions

Background:

• Gemcitabine is a widely used chemotherapy drug.
• Understanding drug-nucleobase interactions is crucial for drug design and predicting efficacy.
• Nucleobases (DNA/RNA components) are potential binding sites for drugs.

Purpose of the Study:

• To investigate the adsorption of gemcitabine on nucleobases.
• To determine the preferred binding configurations and interaction strengths.
• To elucidate the nature of chemical bonding in these complexes.

Main Methods:

• Dispersion-corrected density functional theory (DFT) calculations.
• Analysis of binding and interaction energies.
• Quantum chemical analyses including MESP, QTAIM, HOMA, and NICS.
• Energy decomposition analysis (DLPNO-CCSD(T)).

Main Results:

• Planar gemcitabine-nucleobase complexes are more stable than stacked or buckled configurations.
• Complex formation is an enthalpy-driven process, stabilized by at least two intermolecular hydrogen bonds.
• Gemcitabine-guanine exhibited the strongest binding, while gemcitabine-thymine showed the weakest.
• Intermolecular NH⋅⋅⋅N bonds are particularly strong, possessing partial covalent character.
• Electrostatic attraction is the dominant force, with dispersion playing a minimal role.

Conclusions:

• Gemcitabine can form stable complexes with nucleobases, with varying strengths.
• The interactions are primarily governed by hydrogen bonding and electrostatic forces.
• These findings provide insights into gemcitabine's mechanism of action and potential interactions with genetic material.