title: Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration.
abstract: 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.
authors.affiliation: Departamento de Química, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 917, 5700 San Luis, Argentina.
authors.forename: Rodrigo D
authors.initials: RD
authors.lastname: Tosso
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Andujar
authors.forename: Lucas
authors.initials: L
authors.lastname: Gutierrez
authors.forename: Emilio
authors.initials: E
authors.lastname: Angelina
authors.forename: Ricaurte
authors.initials: R
authors.lastname: Rodríguez
authors.forename: Manuel
authors.initials: M
authors.lastname: Nogueras
authors.forename: Héctor
authors.initials: H
authors.lastname: Baldoni
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Suvire
authors.forename: Justo
authors.initials: J
authors.lastname: Cobo
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Enriz
mesh_terms: D004583:Electrons; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011789:Quantum Theory; D015203:Reproducibility of Results; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase