The electron density obtained from QTAIM analysis acting as a strong molecular descriptor. A molecular modeling study performed in DHFR inhibitors

RODRIGO D. TOSSO; SEBASTIÁN A. ANDUJAR; ADRIANA GARRO; FERNANDO D. SUVIRE; JUAN C. GARRO; RICARDO D. ENRIZ

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists WATOC; 2014

p { margin-bottom: 0cm; direction: ltr; color: rgb(0, 0, 0); text-align: justify; widows: 2; orphans: 2; }p.western { font-family: "Helvetica",sans-serif; font-size: 10pt; }p.cjk { font-family: "Times New Roman",serif; font-size: 10pt; }p.ctl { font-family: "Helvetica",sans-serif; font-size: 10pt; }a:visited { color: rgb(128, 0, 128); }a.western:visited { }a.cjk:visited { }a.ctl:visited { font-family: "Times New Roman",serif; }a:link { color: rgb(0, 0, 255); }a.ctl:link { font-family: "Times New Roman",serif; }a.sdfootnotesym-ctl { font-family: "Times New Roman",serif; }a.sdendnotesym-ctl { font-family: "Times New Roman",serif; } A theoretical study of two new series of inhibitors on human dihydrofolate reductase (DHFR) has been carried out using molecular modeling techniques. First, we performed Molecular Dynamics (MD) simulations on the different ligand-receptor complexes. In the next step, we carried out semiempirical (PM6), ab initio and DFT (Density Functional Theory) calculations using a reduced model of the active site of the enzyme[1]. We also used the umbrella sampling technique to determine the potential of mean force to predict the relative free binding energy of these inhibitors [2]. We found that the relative free energy range is between 10 and 35 kcal/mol, these values agrees with the trend of our experimental assays. All correlations obtained between the binding energies and the IC50 values only allows to differentiate compounds that bind tightly to the enzyme from those which bind very weakly, but are unable to differentiate between compounds that have similar affinities by the enzyme. A similar result was obtained by the study using the umbrella sampling technique. In the last stage of this study, a QTAIM analysis of each complex was performed, which allowed to obtain the electronic density values () of each interaction between the protein and the ligand. From these results, it is possible not only to analyze quantitatively each interaction but also get a correlation using these  values and the IC50 data obtained in our laboratory. This methodology led to a better correlation (R2=0.96) than when the binding energies calculated by quantum mechanical methods were used, allowing to predict the biological activity of novel compounds not yet synthesized with better accuracy.