Quantitative insight into the interactions between propargyl-linked Antifolates and Dihydrofolate Reductase

GUTIÉRREZ LUCAS JOEL; TOSSO RODRIGO; BOMBASARO JOSE; ENRIZ, RICARDO D.

Congreso; 10th Congress of theWorld Association of Theoretical and Computational Chemists (WATOC); 2014

Quantitative insight into the interactions between propargyl-linked Antifolates and Dihydrofolate Reductase Lucas J. Gutierrez,a,c Rodrigo Tossoa,b, José Bombasaroa and Ricardo D. Enriz a,b* a Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina; e-mails: lucasgutierrez10@gmail.com, rdtosso@unsl.edu.ar, jbombasa@unsl.edu.ar; b Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (UNSL-CONICET), Ejercito de Los Andes 950, 5700 San Luis, Argentina; e-mail: denriz@unsl.edu.ar; c Laboratorio de Estructura Molecular y Propiedades, Área de Química Física, Departamento de Química, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste. Av. Libertad 5470, Corrientes (3400), Argentina; e-mail: lucasgutierrez10@gmail.com It is well-known that inhibitors of folate metabolism are quite important drugs in the chemotherapy of bacterial infections and cancer. The effectiveness of antifolates is based on the perturbations they cause in the folate pathway, which rapidly lead to nucleotide imbalance and cell death. Recently, four new compounds with different inhibitory activity have been synthesized and co-crystallized within the DHFR active site [1]. These antifolates include a 2,4-diamino- 6-ethylpyrimidine ring (ring A) and a biaryl ring system (rings B and C) united by a propargyl linker. The ligands differ in the substitution pattern at the propargylic linker (hydrogen or methyl) and the biaryl ring system (3,5-pyrimidine, 4-pyridine, or isoquinoline). In this study, we applied a hybrid Quantum mechanics-Molecular Mechanical (QM-MM) method followed by a Quantum Theory of Atoms in Molecules (QTAIM) analysis to investigate the ligand-receptor interactions of these systems. The affinity of the ligand was evaluated in terms of the electron density ((r)) at the intermolecular bond critical points. In order to validate the methodology used in this work, a correlation between the summatory of (r) and the reported IC50 values was obtained. A correlation coefficient of r2 =0.99 was obtained indicating a high predictive power. A study quantitative of interactions revealed that the interactions of the 2,4-diaminopyrimidine ring are conserved throughout the structures which allow the anchoring of the ligands in the active site. The 4-amino moiety forms a hydrogen bond with the backbone carbonyl oxygen of Ile7 along with a weak hydrogen bond with the backbone carbonyl oxygen of Val115. Both the N1 and the 2-amino group form hydrogen bonds with Glu30. The QTAIM analysis shows us that the difference of activity in these compounds is mainly due to the sum of hydrophobic interactions acting in a cooperative way. These interactions take place between the residues Ile7, Val8, Leu22, Phe31, Phe34 and Leu67 and either the 2,4-diamino- 6-ethylpyrimidine ring or the biaryl ring. Acknowledgments: Universidad Nacional de San Luis, Universidad Nacional del Nordeste and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). References: [1] K.M. Lamb, N. Dayanandan, D.L. Wright, A.C. Anderson, Biochemistry 52(2013)7318.