Quantitative structure-activity relationships of competitive inhibitors of phosphoenolpyruvate carboxylase.

The quantitative structure-activity relationships (QSAR) of all known competitive inhibitors of the enzyme phosphoenolpyruvate carboxylase from C4 plants were investigated by means of molecular mechanics, the semiempirical quantum chemical methods MNDO and AM1, and the Hansch approach. In the case of phosphoenolpyruvate analogues, the hydrophobicity and steric impediment of the combined cis and trans substituents, the bond distance to the cis substituent along with its volume, dipole moment, the distance between the phosphorus and the carbonyl carbon, and the net electric charges on the phosphate and substituent groups are the main factors that govern their binding to the active site. For the phosphoglycolate analogues, the difference in the HOMO-LUMO energies, the magnitudes of their dipole moments and their non-polar surfaces, and the distance between the phosphorus and the carbonyl carbon are the variables that control their binding to the active site. These results, in conjunction with a discriminant analysis, also suggest that these inhibitors can actually be divided into two groups, according to the way they presumably interact with the active site.