Molecular Orbital Descriptors Research Articles

Electrostatics in quantitative structure-activity relationship analysis

Simple ad hoc theoretical molecular descriptors were computed using three semiempirical methods (INDO, MNDO and AM1) for different prototropic forms of two conformationally optimized molecular series of 4-aminodiphenylsulphones and 5-benzyl-2,4-diaminopyrimidines, which are inhibitors of the biosynthesis of folate. The molecular orbital descriptors derived show good linear correlations with the inhibitory potencies of both sulphones (dihydropteroato synthase inhibitors) and benzylpyrimidines (dihydrofolate reductase inhibitors). The results obtained suggest that, in both cases, the electrostatic forces are dominant in the enzyme-inhibitor interaction. However, the role of the substituents in the sulphones considered is mainly connected with the modulation of the electronic structure of the electrostatic pharmacophore 4-NH 2-C 6H 4-SO 2-, whereas in the case of benzylpyrimidines, once the N1 protonated pyrimidine ring recognizes and docks the enzyme active site, both potency and selectivity towards enzyme from different sources are controlled by the substituent pattern on the benzylic ring.