Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

• Published in: Journal of chemical information and modeling Vol. 53; no. 8; pp. 2018 - 2032
• Main Authors: Tosso, Rodrigo D, Andujar, Sebastian A, Gutierrez, Lucas, Angelina, Emilio, Rodríguez, Ricaurte, Nogueras, Manuel, Baldoni, Héctor, Suvire, Fernando D, Cobo, Justo, Enriz, Ricardo D
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 26.08.2013
• Subjects: Chemical compounds; Condensed matter: electronic structure, electrical, magnetic, and optical properties; Correlation analysis; Electron states; Electrons; Exact sciences and technology; Folic Acid Antagonists - pharmacology; Humans; Methods of electronic structure calculations; Molecular Dynamics Simulation; Molecules; Physics; Protein Conformation; Quantum physics; Quantum Theory; Reproducibility of Results; Simulation; Tetrahydrofolate Dehydrogenase - chemistry; Tetrahydrofolate Dehydrogenase - metabolism; Thermodynamics; Energetics; Enzymes; Ab initio method; Quantum wells; Molecular dynamics; Binding site; Experimental study; Electronic structure; Density functional; Molecular physics; Binding energy; Ligands; Modelling; Reduced order systems
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci400178h

A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.