Partial selectivity theoretical approximation of nitric oxide synthase (NOS) isoenzyme sulfur-based inhibitors

Sulfur-based inhibitors of nitric oxide synthases (NOS)such as mercaptoalkylguanidines and isothioureas showed partial selectivity on the enzymes inducible isoform. A computer-based analysis was performed in order to obtain a theoretical explanation for this selectivity. Multivariable regression analysis of molecular structure descriptors and enthalpy changes of the free iron (II) ion complexation derived from semiempirical quantum- chemical estimations as a model for the complexation process of NOS ferrous heme with seven selected inhibitors revealed that NOS isoforms vary in their inhibitory binding effect. The complexation of the iron (II) ion is the most decisive interaction in the inhibition of constitutive isoenzymes, particularly in the case of endothelial isoforms. On the contrary, this complexation is a secondary effect for inducible NO synthase where the structural fitting and polarity of the inhibitor are the most decisive properties.