Ab initio Computational Modeling of Glyphosate Analogs: Conformational Perspective

Abstract

A historical perspective on the application of conformational analysis to structure-based ligand design approach is presented. The application of isodensity molecular electrostatic potential surfaces with the conformational energy surfaces (CES) have allowed us to reach pertinent conclusions for aiding synthetic and biochemical studies. Here we illustrate such an application on the modeling of the potent analogs of an important, environmentally stringent herbicidal compound glyphosate by constructing conformational energy surfaces. The systems were modeled by substituting F, Cl, and NH OH moiety to the position of pharmacophoric nitrogen center in glyphosate structure. All the calculations were thoroughly performed with ab initio MO theory at Hartree-Fock method using 3-21G(d) basis functions. On the basis of the results, we identified the bioactive conformations for N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate as (−38 • , 77 • ), (−61 • , 111 • ), and (−167 • , −169 • ), respectively. Geometry optimization of certain selected conformations of these compounds using hybrid DFT method with 6-31+G(d) basis functions provides nearly equal values of φ and ψ. Moreover, the results indicate that the global minimum structures of N-fluoro and N-chloro analogs of glyphosate show cyclic conformation whereas the N-hydroxyamino-glyphosate global minimum structure shows spyrocyclic and zig-zag conformation. Also, the predicted bioactive conformation of N-hydroxyamino analog optimally overlaps with glyphosate backbone in EPSPS complex with 0.1ÅRMSD value. However, the other two compounds slightly deviate from the backbone of glyphosate with RMSD of 0.92Å for N-fluoro-glyphosate and 0.83Å for N-chloroglyphosate. The linear N-hydroxyamino-glyphosate exhibits relatively more number of intermolecular hydrogen bond interactions as compared to the other two analogs. Further, comparison of CES of previously studied glyphosate analogs such as N-hydroxy-glyphosate (2.2 µM) and N-amino-glyphosate (0.61 µM) with the present systems reveals the order of activity as: N-hydroxyamino-glyphosate > N-fluoro-glyphosate > N-chloro-glyphosate based on CES flexibility. Also, the calculated heats of formation of N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate are −288, −209, and −288 kcal/mol, respectively, which clearly indicate that the N-hydroxyamino and N-fluoro analogs of glyphosate are thermodynamically more stable than N-amino-glyphosate (−278 kcal/mol).

Spectral, structural and energetic study of acephate, glyphosate, monocrotophos and phorate: an experimental and computational approach

“…The computational studies of molecules 1-4 were performed using the Personal Computer-General Atomic and Molecular Electronic Structure System (PC-GAMESS) version 13.0 [4][5][6][7][8][9][10][11][12][13][14]. The theoretical, steric parameters (stretch, bend, stretch-bend, torsion, non-1,4 VDW, 1,4 VDW, dipole/dipole and steric energy for frame), polarizability, infrared intensities (FTIR), UVvisible and 1 H-NMR study of the titled pesticides in the ground state (a minimum energy state of molecule) were calculated.…”

“…The theoretical, steric parameters (stretch, bend, stretch-bend, torsion, non-1,4 VDW, 1,4 VDW, dipole/dipole and steric energy for frame), polarizability, infrared intensities (FTIR), UVvisible and 1 H-NMR study of the titled pesticides in the ground state (a minimum energy state of molecule) were calculated. For the first time, computational analysis was performed using the Hartree Fork (HF) method with the 6-311 ++ G(d,p) basis set through the GAMESS programme [4][5][6][7][8][9][10][11][12][13], using Cambridge Software ChemBio3D Ultra 13.0.…”

“…To analyse these toxic compounds, either on their development stages or in the environmental compartments, it is obligatory to develop theoretical studies to assist the experimental studies. In literature, few studies have been reported to check the spectral, geometrical, toxicological and biodegradation aspects of contaminants/pesticides [2][3][4][5][6][7][8][9][10][11][12][13][14].…”

“…Among these studies, maximum studies were reported on the herbicide, glyphosate. Ali et al [8] have reported an extensive ab initio Molecular Orbital calculations at the HF/3-21G(d) level to study the conformational energy surfaces of Nhydroxy-glyphosate and N-amino-glyphosate [8]. Kaliannan et al [17] have reported fully optimized structure and rotational potential around the active site nitrogen (about the C-N and N-C bond) at the HF/3-21G(d) level [17].…”

Interplay of thermochemistry and Structural Chemistry, the journal (volume 16, 2005) and the discipline

“…In the article by Ali et al [151] efforts have been made to compare the conformational energy surface (CES) characteristics of experimentally studied glyphosate (N-phosphonomethylglycine) analogs with that of the modeled systems; N-fluoro-glyphosate, N-chloroglyphosate, and N-hydroxyamino-glyphosate. The attention is also focused on the nature of molecular electrostatic potential (MEP) maps for the predicted bioactive conformations to identify the electrophilic and nucleophilic regions: predictions are also made for enthalpies of formation.…”